Fused-bicyclic aryl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors

ABSTRACT

The invention relates to inhibitors of mutant isocitrate dehydrogenase (mt-IDH) proteins with neomorphic activity useful in the treatment of cell-proliferation disorders and cancers, having the Formula: 
     
       
         
         
             
             
         
       
     
     where A, B, U, V, Z, W 1 , W 2 , W 3 , and R 1 -R 6  are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalApplication No. 62/150,815, filed Apr. 21, 2015, all of which isincorporated herein by reference in its entirety.

FIELD OF INVENTION

The present invention is directed to inhibitors of mutant isocitratedehydrogenase (mt-IDH) proteins with neomorphic activity useful in thetreatment of diseases or disorders associated with such mutant IDHproteins including cell-proliferation disorders and cancers.Specifically, the invention is concerned with compounds and compositionsinhibiting mt-IDH, methods of treating diseases or disorders associatedwith mt-IDH, and methods of synthesis of these compounds.

BACKGROUND OF THE INVENTION

Isocitrate dehydrogenases (IDHs) are enzymes that participate in thecitric acid cycle (cellular metabolism). They catalyze the oxidativedecarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate,α-KG). There are three isoforms within the IDH family. IDH-1, expressedin the cytoplasm and peroxisome, IDH-2, localized in the mitochondria,both utilize NADP⁺ as the cofactor and exist as homodimers. IDH-3 islocalized in mitochondrial matrix and utilizes NAD⁺ as a cofactor andexists as tetramer. Mutations in IDH-1 (cytosolic) and IDH-2(mitochondrial) have been identified in various diseases or disordersincluding glioma, glioblastoma multiforme, paraganglioma, supratentorialprimordial neuroectodermal tumors, acute myeloid leukemia (AML),prostate cancer, thyroid cancer, colon cancer, chondrosarcoma,cholangiocarcinoma, peripheral T-cell lymphoma, and melanoma (L. Deng etal., Trends Mol. Med., 2010, 16, 387; T. Shibata et al., Am. J. Pathol.,201 1, 178 (3), 1395; Gaal et al., J. Clin. Endocrinol. Metab. 2010;Hayden et al., Cell Cycle, 2009; Balss et al., Acta Neuropathol., 2008).The mutations have been found at or near key residues in the activesite: G97D, R100, R132, H133Q, and A134D for IDH1, and R140 and R172 forIDH2. (See L. Deng et al., Nature, 2009, 462, 739; L. Sellner et al.,Eur. J. Haematol., 2011, 85, 457).

Mutant forms of IDH-1 and IDH-2 have been shown to lose wild typeactivity, and instead exhibit a neomorphic activity (also known as again of function activity), of reducing alpha-ketoglutarate to2-hydroxyglutarate (2-HG). (See P. S. Ward et al., Cancer Cell, 2010,17, 225; Zhao et. al., Science 324, 261 (2009); Dang et. al Nature 462,739 (2009)). In general, production of 2-HG is enantiospecific,resulting in generation of the D-enantiomer (also known as the Renantiomer or R-2-HG). Normal cells have low basal levels of 2-HG,whereas cells harboring mutations in IDH1 or IDH2 show significantlyelevated levels of 2-HG. High levels of 2-HG have also been detected intumors harboring the mutations. For example, high levels of 2-HG havebeen detected in the plasma of patients with mutant IDH containing AML.(See S. Gross et al., J. Exp. Med., 2010, 207 (2), 339). High levels of2-HG have been shown to block α-KG dependent DNA and histonedemethylases, and ultimately to result in improper dedifferentiation ofhematopoietic progenitor cells in AML patients (Wang et. al., Science340, 622 (2013); Losman et al., Science 339, 1621 (2013)).

Furthermore, patients with Oilier Disease and Mafucci Syndrome (two raredisorders that predispose to cartilaginous tumors) have been shown to besomatically mosaic for IDH1 and 2 mutations and exhibit high levels ofD-2-HG. (See Amary et al., Nature Genetics, 2011 and Pansuriya et al.,Nature Genetics, 2011).

The inhibition of mt-IDHs and their neomorphic activity with smallmolecule inhibitors therefore has the potential to be a treatment forcancers and other disorders of cellular proliferation.

SUMMARY OF THE INVENTION

A first aspect of the invention relates to compounds of Formula (I):

and pharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, and tautomers thereof,

wherein:

-   -   each W₁ and W₂ is independently CH, CF, or N;

W₃ is CF, CR₂, or N;

U is N or CR₆;

V is N or CR₉;

Z is N or C;

indicates a single or double bond but never two double bonds adjacent toone another in the ring in which the

occurs;

A and B, A and R₆, or B and R₉ are taken together with the atoms towhich they are attached to form an aryl or a 5 to 7-memberedheterocyclyl or heteroaryl ring system which can be further substitutedwith one or more R₁₀ substituents;

A and B, when not part of the fused aryl, heteroaryl, or 5 to 7-memberedheterocyclyl, are each independently H, R₆, CN, C₁-C₆ alkyl, or C₁-C₆alkoxy;

R₁ is independently H, OH, CN, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, 3 to 8-membered heterocyclyl,aryl, or heteroaryl, wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocyclyl, aryl, or heteroaryl isoptionally substituted one or more times with substituents selected fromthe group consisting of halogen, OH, NH₂, CN, C₁-C₆ alkyl, and C₁-C₆alkoxy;

R₂ is independently H, OH, CN, halogen, CF₃, CHF₂, C₁-C₆ alkyl, C₁-C₆alkoxy, NH₂, —O(CH₂)_(n)R₇, —O(CH₂)_(n)C(O)NHR₇, —O(CH₂)_(n)C(O)R₇,NHR₇, —N(R₇)(R₈), NHC(O)R₇, NHS(O)R₇, NHS(O)₂R₇, NHC(O)OR₇, NHC(O)NHR₇,—S(O)₂NHR₇, NHC(O)N(R₈)(R₇), OCH(R₇)(R₈), or —CH(R₇)(R₈), wherein C₁-C₆alkyl, C₁-C₆ alkoxy is optionally substituted with one or moresubstituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, or 3 to8-membered hetecyclyl substituted with one or more halogen, 3 to8-membered heterocyclyl, aryl, -heteroaryl-C(O)NH₂, and heteroaryl;

R₃ is H or C₁-C₆ alkyl;

R₄ and R₅ are independently H, halogen, CH₂OH, C₁-C₃ alkyl, or C₁-C₃haloalkyl, or R₄ and R₅ when combined can form a C₃-C₆ cycloalkyl or 3to 8-membered heterocyclyl;

R₆ is H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, 3 to8-membered heterocyclyl, aryl, or heteroaryl;

R₇ and R₈ are independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, 3 to 8-membered heterocyclyl, aryl, andheteroaryl; or when combined R₇ and R₈ can form a 3 to 8-memberedheterocyclyl or heteroaryl ring; and

R₉ is independently selected from the group consisting of H, ═O,halogen, OH, CN, —CH₂CN, C₁-C₆ alkyl, R₇S(O)₂—, C₁-C₆ alkoxy, C₂-C₆alkenyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, 3 to8-membered heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkoxy,alkenyl, cycloalkyl, cycloalkylalkyl, 3 to 8-membered heterocyclyl,aryl, and heteroaryl are optionally further substituted with one or moresubstituents selected from the group consisting of OH, halogen, C₁-C₆alkoxy, NH₂, R₇S(O)₂—, CN, C₃-C₈ cycloalkyl, 3 to 8-memberedheterocyclyl, aryl, heteroaryl, and R₇S(O)—;

each R₁₀ is independently H, OH, CN, ═O, —COOR₁₁, —C(O)R₁₁, —CH₂CN,C₁-C₆ alkyl, C₁-C₆ haloalkyl R₁₁S(O)₂—, C₁-C₆ alkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, C₃-C₈heterocyclyl, aryl, or heteroaryl; and

each R₁₁ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl,C₃-C₈ heterocyclyl, aryl, or heteroary; provided that:

(1) when A and B or A and R₆ form a 1,4-dioxane ring, R₁ and R₂ are notboth methyl;

(2) when A and B or A and R₆ form a 1,3-dioxolane ring, R₁ is not H ormethyl;

(3) when A and B or A and R₆ form a pyridine ring, R₁ is not H or R₂ isnot methyl;

(4) when A and B or A and R₆ form a pyrazole ring, R₁ is not H, ethyl,or ethoxy;

(5) when A and B or A and R₆ form a pyrazole ring and R₁ is methyl, R₂is not H; or

(6) when A and B or A and R₆ form a phenyl ring, R₁ is not H.

Another aspect of the invention relates to a method of treating adisease or disorder associated with mutant isocitrate dehydrogenase. Themethod comprises administering to a patient in need of a treatment fordiseases or disorders associated with mutant isocitrate dehydrogenase aneffective amount of a compound of Formula (I).

Another aspect of the invention is directed to a method inhibitingmutant isocitrate dehydrogenase. The method involves administering to apatient in need thereof an effective amount of a compound of Formula(I).

Another aspect of the invention relates to method of reducing2-hydroxyglutarate.

The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I).

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutically acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

The present invention further provides methods of treating cellproliferative diseases and cancers including, without limitation,glioma, glioblastoma multiforme, paraganglioma, supratentorialprimordial neuroectodermal tumors, acute myeloid leukemia (AML),prostate cancer, thyroid cancer, colon cancer, chondrosarcoma,cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepaticcholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS),myeloproliferative disease (MPD), and other solid tumors, comprisingadministering to a patient suffering from at least one of said diseasesor cancers a compound of Formula (I). The inhibitors of the presentinvention may target mutated IDH1 at residue 97, 100 or 132, for exampleG97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. Theinhibitors of the present invention may target mutated IDH2 at residue140 or 172, for example R140Q, R172K, R172M, R172S, R172G, and R172W.

Another aspect of the invention provides for a compound of Formula (I),or a pharmaceutically acceptable salt thereof, in combination withanother therapeutic agent.

BRIEF DESCRIPTION OF THE DRAWINGS OF THE INVENTION

FIG. 1 illustrates a graph showing the potency of IDH1 inhibitors in anIDH1-132H enzyme assay.

DETAILED DESCRIPTION OF THE INVENTION

IDH1 or IDH2 mutations are genetically validated targets in many solidand hematologic cancers, but there are currently no targeted therapiesavailable for patients in need of treatment for specific conditionsassociated with mt-IDH activity. Non-mutant IDH (e.g., wild-type)catalyze the oxidative decarboxylation of isocitrate to α-ketoglutaratethereby reducing NAD⁺ (NADP⁺) to NADH (NADPH) (WO 2013/102431 toCianchetta et al., hereby incorporated by reference in its entirety).Mutations of IDH present in certain cancer cells result in a new abilityof the enzyme to catalyze the NADPH-dependent reduction ofα-ketoglutarate R(−)-2-hydroxyglutarate (2HG). 2HG is not formed bywild-type IDH. The production of 2HG contributes to the formation andprogression of cancer (Dang, L et al., Nature, 2009, 462:739-44, herebyincorporated by reference in its entirety). The present inventionprovides inhibitors of mt-IDH, and prophylactic measures to reduce theformation and progression of 2HG in cells.

In a first aspect of the invention, are described the compounds ofFormula (I):

and pharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, and tautomers thereof, where A, B, U, V, Z, W₁, W₂,W₃, and R₁-R₆ are described as above.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

DEFINITIONS

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g. an alkyl group) can (but is not required to) bebonded other substituents (e.g. heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e. a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, halogen, ═O, CN, —COOH, —CH₂CN,—O—C₁-C₆alkyl, C₁-C₆alkyl, —OC₁-C₆alkenyl, —OC₁-C₆alkynyl,—C₁-C₆alkenyl, —C₁-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆alkyl,—C(O)C₁-C₆alkyl, —OC(O)OC₁-C₆alkyl, NH₂, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂,—NHC(O)C₁-C₆alkyl, —C(O)NHC₁-C₆alkyl, —S(O)₂—C₁-C₆alkyl,—S(O)NHC₁-C₆alkyl, and S(O)N(C₁-C₆alkyl)₂

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 2 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to, —H,-halogen, —O—C₁-C₆alkyl, C₁-C₆alkyl, —OC₁-C₆alkenyl, —OC₁-C₆alkynyl,—C₁-C₆alkenyl, —C₁-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆alkyl,—C(O)C₁-C₆alkyl, —OC(O)OC₁-C₆alkyl, NH₂, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂,—S(O)₂—C₁-C₆alkyl, —S(O)NHC₁-C₆alkyl, and S(O)N(C₁-C₆alkyl)₂. Thesubstituents can themselves be optionally substituted. Furthermore whencontaining two fused rings the aryl groups herein defined may have anunsaturated or partially saturated ring fused with a fully saturatedring. Exemplary ring systems of these aryl groups include indanyl,indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 10 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, or S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl,and derivatives thereof. Furthermore when containing two fused rings thearyl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine, and dihydrobenzoxanyl.

Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms. Examples of a C₁-C₆ alkyl group include,but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl,isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, andisohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms containing a terminal “O” in the chain.Examples of alkoxy groups include without limitation, methoxy, ethoxy,propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkenyl” group contains at least onedouble bond in the chain. Examples of alkenyl groups include ethenyl,propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkynyl” group contains at least onetriple bond in the chain. Examples of alkenyl groups include ethynyl,propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.

“Cycloalkyl” means monocyclic saturated carbon rings containing 3-18carbon atoms. Examples of cycloalkyl groups include, withoutlimitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

“Cycloalkylalkyl” means monocyclic saturated carbon rings containing3-18 carbon atoms further substituted with C₁-C₆ alkyl groups. Ingeneral cycloalkylalkyl groups herein described display the followingformula

where m is an integer from 1 to 6 and n is an integer from 1 to 16.

“Heterocyclyl” or “heterocycloalkyl” monocyclic rings containing carbonand heteroatoms taken from oxygen, nitrogen, or sulfur and wherein thereis not delocalized π electrons (aromaticity) shared among the ringcarbon or heteroatoms; heterocyclyl rings include, but are not limitedto, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.In accordance with the present invention, 3- to 8- membered heterocyclylrefers to saturated or partially saturated non aromatic rings structurescontaining between 3 and 8 atoms in which there is at least oneheteroatoms selected from the group N, O, or S.

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesand as individual enantiomers or diastereomers.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

In one embodiment, the compounds of Formula I have the Formula Ia:

where the C ring is pyrrolidinyl, piperidinyl, phenyl, thienyl,oxazolyl, dioxanyl, dioxolanyl, thiazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl,pyridyl, pyrimidinyl, pyrrolyl, furyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, dazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, pyrimidinyl,morpholinyl, thiomorpholinyl, oxazolonyl, oxazinonyl, dihydrooxazinonyl,imidazolonyl, pyrrolonyl, thiazolonyl, dihydropyridinonyl,dihydrothiazinedioxide, dihydrodioxinyl, dihydropyranonyl,dihydrothiophenedioxide, piperidinonyl, or dihydrooxazinonyl;

R₁₀ is independently H, OH, CN, ═O, —COOR₁₁, —C(O)R₁₁, —CH₂CN, C₁-C₆alkyl, C₁-C₆ haloalkyl R₁₁S(O)₂—, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, C₃-C₈ heterocyclyl,aryl, or heteroaryl; and

each R₁₁ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl,C₃-C₈ heterocyclyl, aryl, or heteroary.

In some embodiments of the compounds of Formula Ia, R₁₀ is methyl,ethyl, isopropyl, or isobutyl.

In another embodiment, the compounds of Formula I have the Formula Ib:

where the C ring is pyrrolidinyl, piperidinyl, phenyl, thienyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl,oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl,pyrrolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, dazolyl,pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, pyrimidinyl, morpholinyl,thiomorpholinyl, oxazolonyl, oxazinonyl, dihydrooxazinonyl,imidazolonyl, pyrrolonyl, thiazolonyl, dihydropyridinonyl,dihydrothiazinedioxide, dihydrodioxinyl, dihydropyranonyl,dihydrothiophenedioxide, piperidinonyl, or dihydrooxazinonyl;

R₁₀ is independently H, OH, CN, ═O, —COOR₁₁, —C(O)R₁₁, —CH₂CN, C₁-C₆alkyl, C₁-C₆ haloalkyl R₁₁S(O)₂—, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, C₃-C₈ heterocyclyl,aryl, or heteroaryl; and

each R₁₁ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl,C₃-C₈ heterocyclyl, aryl, or heteroary.

In some embodiments of any of the foregoing Formula Ib, R₁₀ is methyl,ethyl, isopropyl, or isobutyl.

In some embodiments of any of the foregoing Formula, R₄ and R₅ are H.

In some embodiments of any of the foregoing Formula, R₄ is H and R₅ ismethyl.

In some embodiments of any of the foregoing Formula, R₄ is H and R₅ is(S)-methyl.

In some embodiments of any of the foregoing Formula, R₄ and R₅ arehalogen.

In some embodiments of any of the foregoing Formula, R₄ is F and R₅ ismethyl.

In some embodiments of any of the foregoing Formula R₄ and R₅ cancombine to form a C₃-C₆ cycloalkyl.

In some embodiments of any of the foregoing Formula, W₁, W₂, and W₃ areindependently CH or CF.

In some embodiments of any of the foregoing Formula, W₁, W₂, or W₃ is N.

In some embodiments of any of the foregoing Formula, R₁ can be halogen.

In some embodiments of any of the foregoing Formula, R₁ is chloro.

In some embodiments of any of the foregoing Formula, R₂ can be H orC₁-C₆ alkoxy.

In some embodiments of any of the foregoing Formula, R₂ is C₁-C₆ alkoxysubstituted with heteroaryl or C₃-C₈ heterocyclyl.

In some embodiments of any of the foregoing Formula, illustrativecompounds of the invention include:

-   3-{[(1,3-benzoxazol-4-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(isoquinolin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}naphthalene-1-carbonitrile;-   6-chloro-3-{[(quinolin-8-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2,3-dihydro-1-benzofuran-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   3-({[2-(1H-1,3-benzodiazol-5-yl)-1H-1,3-benzodiazol-5-yl]amino}methyl)-6,7-dimethoxy-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(isoquinolin-8-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3,4-dihydro-2H-1-benzopyran-8-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-1H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-methoxy-3-{[(2-methyl-1,3-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({[1,2,4]triazolo[4,3-b]pyridazin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   3-{[(1H-1,3-benzodiazol-5-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-{[(1,3-benzothiazol-6-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(quinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[2-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   3-{[(1,3-benzothiazol-5-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;-   3-{[(2,3-dihydro-1,4-benzodioxin-6-yl)amino]methyl}-6-methoxy-1,2-dihydroquinolin-2-one;-   3-{[(1H-indazol-6-yl)amino]methyl}-6,7-dimethyl-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-methylquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2,3-dihydro-1,4-benzodioxin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-{[(1H-indazol-6-yl)amino]methyl}-6-methoxy-1,2-dihydroquinolin-2-one;-   6-methoxy-3-{[(2-methylquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-{[(1,3-benzothiazol-6-yl)amino]methyl}-6-methoxy-1,2-dihydroquinolin-2-one;-   6,7-dimethyl-3-{[(2-methylquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-methoxy-3-{[(quinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-{[(1,3-benzothiazol-6-yl)amino]methyl}-6,7-dimethyl-1,2-dihydroquinolin-2-one;-   6-tert-butyl-3-{[(1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-[(1S)-1-({1-acetyl-1H,2H,3H-pyrrolo[3,2-c]pyridin-4-yl}amino)ethyl]-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-methanesulfonyl-1H,2H,3H-pyrrolo[3,2-c]pyridin-4-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   3-[(1S)-1-({1-acetyl-1H,2H,3H-pyrido[3,4-b][1,4]oxazin-5-yl}amino)ethyl]-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[1-(2-methylpropyl)-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-7-methoxy-3-[1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-7-methoxy-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-7-methoxy-3-[(1R)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-7-fluoro-3-[(1R)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydro-1,8-naphthyridin-2-one;-   6-chloro-3-[(1S)-1-{[3-(2-methylpropyl)-2-oxo-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({3-methyl-2-oxo-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-[(9-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-[(8-oxo-8,9-dihydro-7H-purin-2-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({6-oxo-5H,6H,7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({7-methyl-6-oxo-5H,6H,7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;    and-   6-chloro-3-[(1S)-1-({7-oxo-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one.

In another embodiment, illustrative compounds of the invention include:

-   6-chloro-3-[(1S)-1-({1-cyclopropyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[2-oxo-1-(propan-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-1H,3H-2λ⁶,1,5,7-[1λ⁶,2]thiazolo[3,4-d]pyrimidine-2,2-dione;-   6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-1H,3H-2λ⁶,1,5-[1λ⁶,2]thiazolo[4,3-c]pyridine-2,2-dione;-   6-chloro-3-[(1S)-1-({3-methyl-2-oxo-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H-[1,3]thiazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-oxo-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2H,3H-1λ⁶,2,5-[1λ⁶,2]thiazolo[4,5-c]pyridine-1,1-dione;-   5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-1-one;-   6-chloro-3-[(1S)-1-({3-oxo-1H,2H,3H,4H-pyrimido[4,5-c]pyridazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({6-oxo-6H-pyrano[3,2-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H-pyrido[3,4-b]pyrazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({3-oxo-1H,2H,3H,4H-pyrido[4,3-c]pyridazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one-   2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-8-methyl-7,8-dihydropteridin-7-one;-   6-chloro-3-[(1S)-1-({2-methyl-1-oxo-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[6-(2-oxo-1,3-oxazolidin-3-yl)-[1,3]oxazolo[4,5-c]pyridin-4-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-[1,3]oxazolo[4,5-c]pyridine-7-carbonitrile;-   N-(4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-[1,3]oxazolo[4,5-c]pyridin-6-yl)acetamide;-   3-[(1S)-1-[(1H-1,3-benzodiazol-4-yl)amino]ethyl]-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1H-imidazo[4,5-c]pyridin-4-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1H-imidazo[4,5-c]pyridine-7-carbonitrile;-   6-chloro-3-[(1S)-1-({1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({[1,2,4]triazolo[4,3-b]pyridazin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-1H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   6-chloro-3-[(1S)-1-{[1-(2-methylpropyl)-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({3-methyl-2-oxo-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[7-oxo-8-(propan-2-yl)-5H,6H,7H,8H-[1,3]diazino[4,5-d]pyrimidin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({8-ethyl-7-oxo-5H,6H,7H,8H-[1,3]diazino[4,5-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[2-oxo-1-(propan-2-yl)-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   7-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-2,4-dihydro-1H-3,1-benzoxazin-2-one;-   6-chloro-3-[(1S)-1-({1-ethyl-2-oxo-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   7-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2,4-dihydro-1H-3,1-benzoxazin-2-one;-   3-[(1S)-1-({1-acetyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-5-yl}amino)ethyl]-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[1-(2-methylpropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[8-(2-methylpropyl)-7-oxo-5H,6H,7H,8H-[1,3]diazino[4,5-d]pyrimidin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   7-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-(2-methylpropyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one;-   6-chloro-3-[(1S)-1-{[1-(2-methylpropyl)-2-oxo-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-4-(2-methylpropyl)-1,2,3,4-tetrahydroquinoxalin-2-one;-   6-chloro-3-[(1S)-1-{[4-methyl-1-(2-methylpropyl)-3-oxo-1H,2H,3H,4H-pyrido[3,4-b]pyrazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[(4R)-1-methyl-4-(2-methylpropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[9-(2-methylpropyl)-9H-purin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[3-(2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[3-(2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[1-(2-methylpropyl)-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[2-oxo-3-(propan-2-yl)-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[9-(propan-2-yl)-9H-purin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[2-oxo-1-(propan-2-yl)-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-{[6-methyl-7-oxo-8-(propan-2-yl)-5H,6H,7H,8H-[1,3]diazino[4,5-d]pyrimidin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methyl-1-(2-methylpropyl)-1,2,3,4-tetrahydroquinoxalin-2-one;-   6-chloro-3-[(1S)-1-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-2H,3H-[1,3]oxazolo[4,5-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-1H,2H-[1,3]oxazolo[5,4-d]pyrimidin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;-   6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1,4-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one-   6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1,2,3,4-tetrahydroquinoxalin-2-one;-   6-chloro-3-[(1S)-1-[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;-   6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-2-one;-   6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-cyclopropyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-cyclobutyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-ethyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-cyclobutyl-2-oxo-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-cyclopropyl-2-oxo-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({5-methyl-6-oxo-5H,6H,7H,8H-pyrido[3,2-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-(prop-2-yn-1-yl)-1H-1,3-benzodiazol-3-ium;-   6-chloro-3-{[(2-ethynyl-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-ethynyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({1-methyl-2-oxo-1H,2H,3H-pyrrolo[3,2-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({2-oxo-1H,2H,3H-pyrrolo[3,2-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[(1R)-1-oxo-2,3-dihydro-1    X⁴-benzothiophen-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-methyl-1,3-dihydro-2,1-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-[({3-tert-butyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1R)-1-{[1-(2-methylpropyl)-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;-   (4R)-6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-4-(2-methylpropyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-2-one-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-(propan-2-yl)imidazo[1,2-a]pyridin-1-ium;-   6-chloro-3-({[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[3-(propan-2-yl)-2H-indazol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[3-(propan-2-yl)-1,2-benzoxazol-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one-   6-chloro-3-[({3-propyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-ethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[(3    S)-3-ethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[(3    S)-3-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3-ethyl-7-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3-ethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-ethyl-6-methyl-2H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-ethyl-7-methyl-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-methyl-2,3-dihydro-1,2-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-8-carboxamide;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-4-fluoro-2-methyl-1H-1,3-benzodiazol-3-ium;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2,3-dimethylimidazo[1,2-a]pyridin-1-ium;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2,5-dimethylimidazo[1,2-a]pyridin-1-ium;-   6-chloro-3-({[6-(dimethylamino)-8,9-dimethyl-9H-purin-2-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(5-fluoro-2-methyl-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2,7-dimethyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-fluoro-2-methyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3-methyl-1-benzofuran-5-carbonitrile;-   6-chloro-3-({[2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-cyano-1H-1,3-benzodiazol-1-ide;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1H-indole-2-carbonitrile;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}imidazo[1,2-a]pyridine-2-carbonitrile;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1,3-benzothiazole-2-carbonitrile;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2H-indazole-3-carbonitrile;-   5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2H-indazole-3-carbonitrile;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methyl-1H-indole-3-carbonitrile;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-7-methyl-1H-indole-3-carbonitrile;-   5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-7-methyl-1H-indole-3-carbonitrile;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-5-methyl-1H-indole-3-carbonitrile;-   3-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}isoquinoline-8-carbonitrile;-   6-chloro-3-{[(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-oxo-2,3-dihydro-1,3-benzoxazole-7-carboxamide;-   6-chloro-3-{[(7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methoxy-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({4-methyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({2-oxo-2H,3H-[1,3]oxazolo[4,5-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-oxo-2H-chromene-8-carboxamide;-   6-chloro-3-{[(8-methyl-2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(8-methoxy-2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one-   6-chloro-3-[({8-methyl-2-oxo-2H-pyrano[2,3-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one-   5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-7-carboxamide;-   6-chloro-3-{[(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({1,4-dimethyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3-methyl-2-oxo-2H,3H-[1,3]oxazolo[4,5-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[2-(hydroxymethyl)-1,3-benzoxazol-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[3-(hydroxymethyl)-1,2-benzoxazol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-hydroxy-1-benzothiophen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}isoquinoline-5-carboxylate;-   4-chloro-5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1H-1,3-benzodiazol-3-ium;-   3-chloro-6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}imidazo[1,2-a]pyridin-1-ium;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-7-formylimidazo[1,2-a]pyridin-1-ium;-   6-chloro-3-[({2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(6-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(5-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-6-cyano-1H-1,3-benzodiazol-3-ium;-   6-chloro-5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1H-1,3-benzodiazol-3-ium;-   7-chloro-5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1H-1,3-benzodiazol-3-ium;-   6-chloro-3-{[(7-methyl-1H-1,2,3-benzotriazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methoxy-1H-1,2,3-benzotriazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-ethyl-2H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-ethyl-2H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(6-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(6-methyl-1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(6-methyl-1-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(6-fluoro-2-methyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[6-(dimethylamino)-1H-indol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(6-hydroxy-3-methyl-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methyl-1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methyl-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3,7-dimethyl-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-cyclopropyl-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methoxy-3-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methoxy-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-oxo-1,3-dihydro-2-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[(3R)-3-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-oxo-2,3-dihydro-1-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   6-chloro-3-({[(1R)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[(1R)-1-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[(1S)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({2,4,5,7-tetraazatricyclo[6.4.0.0^(2,) ⁶    ]dodeca-1(12),3,5,8,10-pentaen-11-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-cyclopropyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-cyclopropyl-1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-methyl-1H-1,2,3-benzotriazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-hydroxy-1H-1,2,3-benzotriazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-oxo-2,3-dihydro-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-1-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-{[(1,2-benzoxazol-5-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methoxy-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-hydroxy-1-benzothiophen-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-1,2-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-7-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1H,2H,3H,4H-pyrido[2,3-d]pyrimidine-2,4-dione;-   6-chloro-3-[({1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[5-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({1-methyl-2-oxo-1H,2H,3H-pyrrolo[2,3-c]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({2-oxo-1H,2H,3H-pyrrolo[2,3-c]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({2-oxo-2H-pyrano[2,3-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({1-methyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1,5-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methyl-1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(5-methyl-2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methyl-1-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-fluoro-3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methoxy-7-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methoxy-1-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[(3R)-3-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-cyclopropyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methoxy-1H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3-methyl-2H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3-cyclobutyl-[,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-4-methyl-1,2-dihydro-1,8-naphthyridin-2-one;-   6-chloro-3-{[(1,8-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(3,4-dimethyl-1,2-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(8-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1,5-naphthyridin-2-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(quinoxalin-2-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[6-(thiophen-2-yl)-9H-purin-2-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[6-(furan-3-yl)-9H-purin-2-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[6-(morpholin-4-yl)-9H-purin-2-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({4,7-dimethyl-5-oxo-5H,6H-pyrimido[4,5-d][1,3]diazin-2-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-hydroxy-1,2,4-benzotriazin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(5-methyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(5-ethyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-ethyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({5-fluoro-1H-pyrrolo[2,3-b]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   3-[({4-bromo-1H-pyrrolo[2,3-b]pyridin-6-yl}amino)methyl]-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   3-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}quinoxaline-2-carbonitrile;-   6-chloro-3-{[(5-methyl-1-benzofuran-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methoxy-1-benzofuran-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1,6-naphthyridin-2-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-methyl-1H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1,2-benzoxazole-7-carbonitrile;-   6-chloro-3-{[(7-methyl-1,2-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-{[(1,2-benzoxazol-6-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methyl-1,2-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3H-imidazo[4,5-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(6-chloro-9H-purin-2-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[6-(dimethylamino)-9H-purin-2-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({imidazo[1,2-a]pyrazin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({imidazo[1,2-b]pyridazin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3-methyl-3H-imidazo[4,5-b]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[5-(methylsulfanyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   3-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-[1,2,4]triazolo[3,2-c][1,2,4]triazin-4-olate;-   6-chloro-3-[({[1,2,4]triazolo[1,5-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4,7-dimethyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(5-hydroxy-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-{[(1,3-benzoxazol-6-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;-   3-{[(1,3-benzoxazol-5-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(6-methyl-1,3-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-hydroxy-1,3-benzothiazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methyl-1,3-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   3-[({8-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[3-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({5-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({7-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({7-methyl-[1,2,3,4]tetrazolo[1,5-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({[1,2,3,4]tetrazolo[1,5-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   3-{[(1,2,3-benzoxadiazol-6-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(5-fluoro-1,2,3-benzothiadiazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-{[(2,1,3-benzoxadiazol-5-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(6-methyl-2,1,3-benzothiadiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methyl-2,1,3-benzothiadiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-methyl-2,1,3-benzothiadiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(4-hydroxy-2,1,3-benzothiadiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[7-(propan-2-yl)-1,3-benzoxazol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methyl-1,3-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(7-methyl-1,3-benzothiazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-1H,2H,3H-pyrrolo[3,2-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-1H,2H,3H-pyrrolo[2,3-c]pyridin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-1H,2H,3H-pyrrolo[2,3-b]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-1H,2H,3H-pyrrolo[3,2-b]pyridin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-2H,3H-[1,3]oxazolo[4,5-b]pyridin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-1H,2H-[1,3]oxazolo[5,4-b]pyridin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-5H,7H-6λ⁶,1,3-[1λ⁶]thieno[3,4-d]pyrimidine-6,6-dione;-   6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1H,3H-2λ⁶,1,5,7-[1λ⁶,2]thiazolo[3,4-d]pyrimidine-2,2-dione;-   2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-5H,6H,8H-7λ⁶,1,3-[1λ⁶]thiopyrano[3,4-d]pyrimidine-7,7-dione;-   2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-5H,7H,8H-6λ⁶,1,3-[1λ⁶]thiopyrano[4,3-d]pyrimidine-6,6-dione;-   6-chloro-3-[(1S)-1-({6-methyl-7-oxo-5H,6H,7H,8H,9H-pyrimido[4,5-e][1,4]diazepin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({5H,6H,7H,8H,9H-pyrimido[4,5-b]azepin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({3-methyl-2-oxo-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   6-chloro-3-[({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)methyl]-1,2-dihydroquinolin-2-one;-   (S)-7-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-6H-pyrido[1,2-a]pyrazin-6-one;-   (S)-6-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-5H-[1,2,4]oxadiazolo[4,5-a]pyridin-5-one;-   (S)-6-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-5-one;-   (S)-6-chloro-3-(1-((5-oxo-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)amino)ethyl)quinolin-2(1H)-one;    and-   (S)-6-chloro-3-(1-((5-oxo-1,5-dihydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)ethyl)quinolin-2(1H)-one.

In another embodiment of the invention, the compounds of Formula (I) areenantiomers. In some embodiments the compounds are the (S)-enantiomer.In other embodiments the compounds are the (R)-enantiomer. In yet otherembodiments, the compounds of Formula (I) may be (+) or (−) enantiomers.

In another embodiment of the invention, the compounds of Formula Icontain isotopes of atoms forming the structure of Formula I. Isotopesherein means, each of two or more forms of the same element (e.g., H andD; ¹²C and ¹³C) that contain equal numbers of protons but differentnumbers of neutrons in their nuclei, and hence differ in relative atomicmass.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Method of Synthesizing the Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M.

Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley,New York 1999). These groups are removed at a convenient stage of thecompound synthesis using methods that are readily apparent to thoseskilled in the art. The selection processes, as well as the reactionconditions and order of their execution, shall be consistent with thepreparation of compounds of Formula (I).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula (I). Accordingly, the present invention includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Compounds of thepresent invention formula (I) can be synthesized by following the stepsoutlined in Schemes 1-2, which comprise different sequences ofassembling intermediates II, III, IV, V, and VI. Starting materials areeither commercially available or made by known procedures in thereported literature or as illustrated.

wherein A, B, U, V, R₁-R₁₀, W₁, W₂, and W₃ are defined in Formula (I)

The general ways of preparing target molecules Ia and Ib by usingintermediates II, III, IV, V, and VI are outlined in Scheme 1-2.Reductive amination of aldehyde (II) with amine (IVa & IVb) is performedunder standard procedure (AcOH and NaBH(OAc)₃) to prepare the compoundof formula I (Ia & Ib). Displacement of aryl halides (V & VI) withintermediates amine (III) under standard nucleophilic substitutionconditions using base such as N,N-diisopropylethylamine, and/orpotassium carbonate, cesium carbonate in solvent DMSO or DMF gives thecompounds of Formula I (Ia & Ib). A mixture of enantiomers,diastereomers, cis/trans isomers resulted from the process can beseparated into their single components by chiral salt technique,chromatography using normal phase, reverse phase or chiral column,depending on the nature of the separation.

It should be understood that in the description and formulae shownabove, the various groups A, B, W₁, W₂, W₃, U, V, Z, and R₁-R₁₀ andother variables are as defined above, except where otherwise indicated.Furthermore, for synthetic purposes, the compounds of schemes 1 and 2are mere representative with elected radicals to illustrate the generalsynthetic methodology of the compound of formula I as defined herein.

Methods of Using the Disclosed Compounds

Another aspect of the invention relates to a method of treating adisease or disorder associated with mutant isocitrate dehydrogenase. Themethod involves administering to a patient in need of a treatment fordiseases or disorders associated with mutant isocitrate dehydrogenase aneffective amount of the compositions and compounds of Formula (I).

Another aspect of the invention is directed to a method of inhibitingmutant isocitrate dehydrogenase. The method involves administering to apatient in need thereof an effective amount of a compound of Formula(I).

Examples of a mutant IDH protein having a neomorphic activity are mutantIDH1 and mutant IDH2. A neomorphic activity associated with mutant IDH1and mutant IDH2 is the ability to produce 2-hydroxyglutarate (2-HGneomorphic activity), specifically R-2-HG (R-2-HG neomorphic activity).Mutations in IDH 1 associated with 2-HG neomorphic activity,specifically R-2-HG neomorphic activity, include mutations at residues97, 100, and 132, e.g. G97D, R100Q, R132H, R132C, R132S, R132G, R132L,and R132V. Mutations in IDH2 associated with 2-HG neoactivity,specifically R-2-HG neomorphic activity, include mutations at residues140 and 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.

Another aspect of the invention relates to method of reducing2-hydroxyglutarate. The method comprises administering to a patient inneed thereof an effective amount of a compound of Formula (I).

One therapeutic use of the compounds or compositions of the presentinvention which inhibit mt-IDH is to provide treatment to patients orsubjects suffering from cell proliferative diseases and cancersincluding, without limitation, glioma, glioblastoma multiforme,paraganglioma, supratentorial primordial neuroectodermal tumors, acutemyeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer,chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma,melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplasticsyndrome (MDS), myeloproliferative disease (MPD), and other solidtumors.

Targeted treatments for these cancers and cell proliferative diseasesare not currently available to patients suffering from these conditions.Therefore, there is a need for new therapeutic agents selective to theseconditions.

The disclosed compounds of the invention can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Table 6 provides activity of illustrative compounds of Formula I inIDH1-R132H, IDH1-R132C, IDH1-MS-HTC116-R132H, and IDH1-MS-HTC116-R132Cassays.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on either Bruker or Varian spectrometers at 300 MHz.Spectra are given in ppm (δ) and coupling constants, J, are reported inHertz. Tetramethylsilane (TMS) was used as an internal standard. Massspectra were collected using a Waters ZQ Single Quad Mass Spectrometer(ion trap electrospray ionization (ESI)). High performance liquidchromatograph (HPLC) analyses were obtained using a XBridge Phenyl orC18 column (5 μm, 50×4.6 mm, 150×4.6 mm or 250×4.6 mm) with UV detection(Waters 996 PDA) at 254 nm or 223 nm using a standard solvent gradientprogram (Method 1-4).

LCMS Method 1 (ESI, 4 Min Method): Instruments:

HPLC: Waters MS: Waters ZQ Single Quad Mass Spectrometer HT2790 AllianceUV: Waters 996 PDA 95% water/5% methanol with 0.1% Formic Acid

Conditions:

Mobile phase A Mobile phase B (B) 95% methanol/5% water with 0.1% FormicAcid Column XBridge Phenyl or C18, 5 μm 4.6 × 50 mm Column temperatureAmbient LC gradient Linear 5-95% B in 2.5 min, hold 95% B to 3.5 min LCFlow rate 3 mL/min UV wavelength 220 nm and 254 nm Ionization ModeElectrospray Ionization; positive/negative

LCMS Method 2 (ESI, 10 Min Method): Instruments:

HPLC: Waters HT2790 Alliance MS: Waters ZQ Single Quad Mass SpectrometerUV: Waters 996 PDA

Conditions:

Mobile phase A (A) 95% water/5% methanol with 0.1% Formic Acid Mobilephase B (B) 95% methanol/5% water with 0.1% Formic Acid Column XBridgeC18, 5 μm 4.6 × 150 mm Column temperature Ambient LC gradient Linear5-95% B in 5.5 min, hold 95% B to 7.5 min LC Flow rate 1.2 mL/min UVwavelength 220 nm and 254 nm Ionization Mode Electrospray Ionization;positive/negative

LCMS Method 3: (APCI, 20 Min) Instruments and Conditions:

HPLC-Agilent 1100 series.Column: Agela Technologies Durashell C18, 3 μm, 4.6×50 mm,).

Mobile Phase A: ACN+0.1% TFA. Mobile Phase B: Water+0.1% TFA.

Time (min) % B Gradient: 00 95 15 05 18 05 20 95Flow Rate: 1 mL/min.

ColumnTemperature: Ambient. Detector: 254 nm. LCMS Method 4 (ESI, 2.5Min Method): Instruments and Conditions:

HPLC: Waters Acquity MS: Waters ZQ Mass Detector Binary Solvent ManagerUV: Waters Acquity PDA Mobile phase A (A) 95% water/5% acetonitrile with0.1% formic acid in 10 mM ammonium formate Mobile phase B (B) 95%acetonitrile/5% water with 0.09% formic acid Column Waters Acquity UPLCBEH C18, 1.7 μm, 2.1 × 50 mm Column temperature 35° C. LC gradient5-100% B in 2.0 min, hold 100% B to 2.2 min LC Flow rate 0.6 mL/min UVwavelength 220 nm and 254 nm Ionization Mode Electrospray Ionization;positive/negative

ABBREVIATIONS USED IN THE FOLLOWING EXAMPLES AND ELSEWHERE HEREIN ARE

-   Ac₂O acetic anhydride-   ACN Acetonitrile-   BOP ammonium 4-(3-(pyridin-3-ylmethyl)ureido)benzenesulfinate-   CDCl₃ deuterated chloroform-   CDI 1,1′-Carbonyldiimidazole-   Cs₂CO₃ cesium carbonate-   CuSO₄ copper sulfate-   δ chemical shift-   DCM dichloromethane or methylene chloride-   DCE 1,2-dichloroethane-   DEAD diethyl azodicarboxylate-   DIAD diisopropyl azodicarboxylate-   DIEA N,N-diisopropylethylamine-   DMA N,N-dimethylacetamide-   DME dimethoxyethane-   DMF N,N-dimethylformamide-   DMP Dess-Martin Periodinane-   DMSO dimethylsulfoxide-   DMSO-d₆ deuterated dimethylsulfoxide-   dppf 1,1′-Bis(diphenylphosphino)ferrocene-   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   ee enantiomeric excess-   EtOAc ethyl acetate-   EtOH ethanol-   ¹H NMR proton nuclear magnetic resonance-   HOAc acetic acid-   HATU    2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium    hexafluorophosphate-   HCl hydrochloric acid-   HOBT 1H-benzo[d][1,2,3]triazol-1-ol hydrate-   HPLC high pressure liquid chromatography-   Hz hertz-   IPA isopropyl alcohol-   KOAc potassium acetate-   K₂CO₃ potassium carbonate-   LAH lithium aluminum hydride-   LCMS liquid chromatography/mass spectrometry-   (M+1) mass+1-   m-CPBA m-chloroperbenzoic acid-   MeOH methanol-   MeMgBr methyl magnesium bromide-   MS mass spectrometry-   NaBH₄ sodium borohydride-   Na₂SO₄ sodium sulfate-   Pd(dppf)Cl₂    [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Palladium tetrakis Tetrakis(triphenylphosphine)palladium(0)-   Rt retention time-   TBDMS-Cl Tert-butyl dimethylsilyl chloride-   TEA triethylamine-   THF tetrahydrofuran-   TLC thin layer chromatography-   Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Example 1 Intermediate III-1:(S)-3-(1-aminoethyl)-6-chloroquinolin-2(H)-one hydrochloride

Step-1:(R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide

To a mixture of 2,6-dichloroquinoline-3-carbaldehyde (15.0 g, 66.37mmol) and (R)-2-methylpropane-2-sulfinamide (8.85 g, 73.14 mmol) in1,2-dichloroethane (150 mL) was added CuSO₄ (16.0 g, 100.25 mmol). Theresulting mixture was heated to 55° C. and stirred at 55° C. overnight.After TLC and MS showed complete disappearance of starting materials,the mixture was cooled to room temperature and filtered through a pad ofCelite®. The pad of celite was then rinsed with CH₂Cl₂. The filtrate wasevaporated to dryness in vacuo and purified by SiO₂ columnchromatography (0 to 25% hexanes/EtOAc) to afford the title compound,(R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide,as a yellow solid (17.7 g, 81% yield).

Step-2:(R)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(8.85 g, 26.88 mmol) in anhydrous CH₂Cl₂ (200 mL) at −60 OC was addeddrop wise MeMgBr (3M solution in diethyl ether, 13.5 mL, 40.54 mmol).The resulting reaction mixture was stirred at about −60 to −50° C. for 3hours and then stirred at −20 OC overnight under an atmosphere of N₂.After TLC and MS showed complete disappearance of starting materials,saturated NH₄Cl (163 mL) was added at −20° C. and the resulting mixturewas stirred for 10 minutes. The aqueous phase was extracted with CH₂Cl₂(100 mL×3), dried over anhydrous Na₂SO₄, filtered, and evaporated. Theresidue was purified by column chromatography on an ISCO® chromatographysystem (SiO₂: Gold column; gradient; hexanes to 100% EtOAc) to providethe title compound,(R)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide,as a yellow solid (5.8 g, 63% yield).

Step-3: (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride(III-1)

A mixture of(R)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(6.6 g, 19.13 mmol) in 1,4-dioxane (41 mL) and 1N HCl (41 mL) was heatedat reflux overnight. The solvents were evaporated in vacuo and theresulting residue was dissolved in hot water and lyophilized. The crudeproduct was triturated with diethyl ether to afford the title compoundIII-1 as a yellow solid (quant. yield, ee: 98.4%). ¹H NMR (300 MHz,DMSO-d₆): δ ppm 12.4 (br s, 1H), 8.32 (br s, 2H), 8.07 (s, 1H), 7.85 (d,J=2.2 Hz, 1H), 7.63 (dd, J₁=8.8 Hz, J₂=2.5 Hz, 1H), 7.40 (d, J=8.8 Hz,1H), 4.40-4.45 (m, 1H), 1.53 (d, J=8.5 Hz, 3H). LCMS (Method 3): Rt 3.42min, m/z 223.1 [M+H]⁺.

Example 2 Intermediate III-2:(R)-3-(1-aminoethy)-6-chloroquinolin-2(1H)-one hydrochloride

Step-1:(R)—N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide

To a mixture of 2,6-dichloroquinoline-3-carbaldehyde (500 mg, 2.21 mmol)and (R)-2-methylpropane-2-sulfinamide (295 g, 2.43 mmol) in1,2-dichloroethane (15 mL) was added CuSO₄ (530 mg, 3.31 mmol). Theresulting mixture was heated to 55° C. and stirred at 55° C. for 18hours. Once TLC and MS showed complete disappearance of startingmaterials, the reaction mixture was cooled to room temperature andfiltered through a pad of Celite®. The pad of celite was then rinsedwith CH₂Cl₂. The filtrate was evaporated to dryness in vacuo andpurified by column chromatography on an ISCO® chromatography system(SiO₂; hexanes to 60% EtOAc/hexanes) to afford the title compound,(R)—N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide,as a yellow solid (510 mg,70% yield).

Step-2:(R)—N—((R)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R)—N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(505 mg, 1.534 mmol) in anhydrous THF (8 mL) at 0° C. was added dropwise MeMgBr (3M solution in diethyl ether, 0.56 mL, 1.687 mmol). Themixture was stirred at 0° C. for 3 hours under an atmosphere of N₂.After TLC and MS showed complete disappearance of starting materials,saturated NH₄Cl (5 mL) was added at 0° C. and the resulting mixture wasstirred for 10 minutes. The aqueous phase was extracted with EtOAc (10mL×3), dried over anhydrous Na₂SO₄, filtered, and evaporated. Theresidue was purified by column chromatography on an ISCO® chromatographysystem (SiO₂: hexanes to 80% EtOAc/hexanes) to afford the title compoundas the R,R isomer as a pale yellow solid (200 mg, 38%) and the R,Sisomer as a pale yellow solid (93 mg, 18% yield).

Step-3: (R)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride(III-2)

A mixture of(R)—N—((R)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(190 mg, 0.55 mmol) in 1,4-dioxane (2 mL) and 1N HCl (1.1 mL, 1.1 mmol)was heated to 150° C. for 30 minutes in a microwave reactor. Thesolvents were evaporated and the residue was dissolved in hot water andlyophilized to afford the title compound III-2 as a yellow solid (148mg, quantitative yield). 1H NMR (300 MHz, DMSO-d₆): δ ppm 12.35 (br s,1H), 8.28 (br s, 2H), 8.05 (s, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.63 (dd,J₁=8.8 Hz, J₂=2.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.40-4.45 (m, 1H),1.53 (d, J=8.5 Hz, 3H). LCMS (Method 3): Rt 3.40 min, m/z 223.1 [M+H]⁺.

Example 3 An Alternative Approach to Intermediate III-1

Step-1: 3-acetyl-6-chloroquinolin-2(1H)-one

A mixture of 2-amino-5-chlorobenzaldehyde (0.5 g, 3.21 mmol) and2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.594 g, 4.18 mmol) in xylenes (10mL) under an atmosphere of nitrogen was heated to reflux for 3 hours andthen cooled to room temperature. The reaction mixture was filtered andwashed with xylenes twice to afford the title compound,3-acetyl-6-chloroquinolin-2(1H)-one (330 mg, 46.3%). ¹H NMR (300 MHz,DMSO-d₆): δ ppm 12.22 (br, 1H), 8.41 (s, 2 H), 8.00 (s, 1H), 7.63 (d,J=8.8 Hz, 1H), 7.32 (dd, J₁=8.8 Hz, J₂=2.5 Hz, 1H), 2.58 (s, 3H). LCMS(Method 1): m/z 222.94 [M+H]⁺.

Step-2:((S)—N—((S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

A mixture of tetraethoxytitanium (144 mg, 0.632 mmol),(S)-2-methylpropane-2-sulfinamide (38.3 mg, 0.316 mmol), and3-acetyl-6-chloroquinolin-2(1H)-one (70 mg, 0.316 mmol) in THF (20 mL)was heated to 80° C. overnight and then cooled to room temperature. Tothis mixture was added NaBH₄ (59.7 mg, 1.579 mmol) at −50° C. Themixture was then slowly warmed up to room temperature overnight. MeOH (2mL) was added to quench excess NaBH₄ and was followed by the addition ofwater. The resulting mixture was filtered to remove solids and theaqueous phase was extracted with EtOAc twice, dried over Na₂SO₄ andconcentrated. The residue was purified on a Biotage® chromatographysystem using a 25 g SiO₂ column with gradient elution (20% to 100%EtOAc/Hexanes, then 0-5% MeOH/DCM) to afford(S)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(39 mg, 38% yield). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.05 (br, 1H),7.95 (s, 1H), 7.84 (s, 1H), 7.38 (d, J=8.8 Hz, 1H), 5.76 (d, J=8.06 Hz,1H), 5.37 (m, 1H), 4.55 (m, 1H), 1.44 (d, J=6.82 Hz, 3H), 1.18 (s, 9H).LCMS (Method 1): Rt 2.22 min; m/z 327.96 [M+H]⁺. Step-3:(S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride (III-1).

To a solution of((S)—N—((S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (150 mg, 0.459 mmol) in MeOH (5 mL) was added HCl(2 mL, 8.0 mmol, 4M in 1,4-dioxane). The mixture was stirred at roomtemperature overnight. To this mixture was added 6 mL of ethyl ether andthe resulting precipitate was collected by filtration, washed with ethylether (2 x), and then dried to afford(S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride (50 mg,42% yield). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.4 (br s, 1H), 8.32 (brs, 2H), 8.07 (s, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.63 (dd, J₁=8.8 Hz,J₂=2.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.40-4.45 (m, 1H), 1.53 (d,J=8.5 Hz, 3H). LCMS (Method 1): Rt 1.22 min, m/z 223.1 [M+H]⁺.

Example 4 Alternate Approach(R)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride (III-2)

Step-1:((R)—N—((R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

A mixture of tetraethoxytitanium (412 mg, 1.805 mmol)(R)-2-methylpropane-2-sulfinamide (131 mg, 1.083 mmol) and3-acetyl-6-chloroquinolin-2(1H)-one (160 mg, 0.722 mmol) in THF (20 mL)was heated to 80° C. overnight, then cooled to room temperature. To thismixture was added NaBH₄ (137 mg, 3.61 mmol) −50° C. The mixture was thenslowly warmed up to room temperature overnight. MeOH (2 mL) was added toquench excess NaBH₄ and was followed by the addition of water. Theresulting mixture was filtered to remove solids and the aqueous phasewas extracted with EtOAc twice, dried over Na₂SO₄ and concentrated. Theresidue was purified on a Biotage® chromatography system using a 25 gSiO₂ column with gradient elution (20 to 100% EtOAc/Hexanes, then 0-5%MeOH/DCM) to afford((R)—N—((R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (157 mg, 66% yield). ¹H NMR (300 MHz, CDCl₃): δppm 11.31 (br, 1H), 7.35 (s, 1H), 7.07-7.22 (m, 2H), 5.86 (d, J=9.3 Hz,1H), 5.37 (m, 1H), 4.55 (m, 1H), 1.56 (d, J=6.94 Hz, 3H), 1.32 (s, 9H).

LCMS (Method 1): Rt 2.20 min, m/z 327.96 [M+H]⁺.

Step-2: (R)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride(III-2)

To a solution of(R)—N—((R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(150 mg, 0.459 mmol) in MeOH (5 mL) was added HCl (2 mL, 8.00 mmol, 4Min 1,4-dioxane). The mixture was stirred at room temperature overnight.To this mixture was added 6 mL of ethyl ether and the resultingprecipitate was collected by filtration, washed with ethyl ether (2×),and then dried to afford (R)-3 (1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride (80 mg, 67% yield). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.32(br s, 1H), 8.34 (br, 2H), 8.06 (s, 1H), 7.81 (s, 1H), 7.58 (d, J=8.82Hz, 1H), 7.31 (d, J=8.83 Hz, 1H), 4.40-4.45 (m, 1H), 1.53 (d, J=6.81 Hz,3H). LCMS (Method 1): Rt 1.20 min, m/z 223.1 [M+H]⁺.

Example 5 Intermediate III-3:(S)-3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-one

Step-1: 2-Amino-5-chloro-4-fluorobenzoic acid

2-Amino-4-fluorobenzoic acid (50 g, 322.6 mmol) was dissolved in 700 mLof DMF and N-chlorosuccinimide (41 g, 305.5 mmol) was added portionwise. The reaction mixture was heated at 50° C. for 5 h. The mixture wascooled to room temperature, poured on to ice cold water to get thesolid. The solid was filtered and dissolved in EtOAc, then sat. NaCl(300 mL) was added. The aqueous layer was extracted with EtOAc (3×200mL). The combined organic phase was dried (Na₂SO₄) and evaporated to abrown solid (42 g, 69%) as desired product2-amino-5-chloro-4-fluorobenzoic acid.

Step-2: (2-Anmino-5-chloro-4-fluorophenyl)methanol

2-Amino-5-chloro-4-fluorobenzoic acid (42 g, 221 mmol) was dissolved in100 mL of THF and BH₃.THF (712 mL of 1 M solution in THF, 712 mmol) wasadded drop wise over the period of 1 h at room temperature. The reactionmixture was heated at 50° C. overnight (18 h). The mixture was cooled toroom temperature, poured onto ice cold water, and sat. NaCl solution wasadded. The aqueous was extracted with EtOAc (3×200 mL). The combinedorganic phase was dried (Na₂SO₄), evaporated and purified by flashchromatography using 0-100% hexanes/ethyl acetate as eluent to affordthe desired product as a brown solid (17 g, 45%).

Step-3: 2-Amino-5-chloro-4-fluorobenzaldehyde

To a solution of (2-amino-5-chloro-4-fluorophenyl)methanol (22 g, 125.7mmol) in 1000 mL of chloroform was added MnO₂ (109 g, 1250 mmol) and thereaction mixture was stirred overnight at ambient temperature. Thereaction mixture was filtered, washed with EtOAc and evaporated. Theresulting crude product was passed through a pad of silica gel elutingwith 0 to 20% hexanes/EtOAc to give the pure product as a brown solid(19 g, 87%).

Step-4: 3-acetyl-6-chloro-7-fluoroquinolin-2(1H)-one

A mixture of 2-Amino-5-chloro-4-fluorobenzaldehyde (14 g, 173.6 mmol)and 2,2,6-trimethyl-4H-1,3-dioxin-4-one (16 mL, 121 mmol) in m-xylene(500 mL) was refluxed for 1.5 h. The reaction mixture was cooled to roomtemperature and filtered. The collected solid was washed with m-xyleneand dried to yield the desired product (9.6 g, 50%) as off-white solid.

Step-5:(S)—N—((S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a mixture of 3-acetyl-6-chloro-7-fluoroquinolin-2(1H)-one (6.4 g,26.7 mmol) and (S)-2-methylpropane-2-sulfinamide (4.85 g, 40.06 mmol) inTHF (450 mL) was added Ti(OEt)₄ (14 mL, 66.7 mmol). The resultantmixture was stirred at 80° C. overnight. Upon the completion of thereaction, the reaction mixture was cooled to −60° C. and NaBH₄ (5.1 g,134 mmol) was added portion wise and then allowed to warm to roomtemperature overnight. The excess NaBH₄ was quenched with MeOH (20 mL),then with water (20 mL) and EtOAc (300 mL). The solution was filteredthrough a pad of celite. The filtrate was taken into a separatory funneland the organic layer was separated, dried (Na₂SO₄), concentrated andpurified by flash chromatography (SiO₂: hexanes/^(i)PrOH 0 to 20%) togive the title compound (4.5 g, 49%) as a yellow solid.

Step-6: (S)-3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-one. HCl,III-3

To a mixture of(S)—N—((S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (3.5 g, 10.1 mmol) in MeOH (80 mL) was added 3Nmethanolic HCl (80 mL, 121 mmol). The resultant mixture was stirred atroom temperature overnight. To this mixture was added diethyl ether (60mL) and the resulting solid was filtered and dried to give the desiredproduct III-3 (2.1 g, 75%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆):δ 12.40 (br s, 1H), 8.24 (br s, 2H), 8.07-8.05 (m, 2H), 7.32 (d, J=10.4Hz, 1H), 4.5-4.15 (m, 1H), 1.53 (d, J=6.8 Hz, 3H). LCMS (method LCMS3,APCI): Rt 3.47 min, m/z 241.1 [M+H]⁺.

Example 6 Intermediate III-4:3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-one

Step 1: 2,6-dichloro-7-methoxyquinoline-3-carbaldehyde

A tube was capped with a septum and placed under an atmosphere ofnitrogen. DMF (6.4 mL, 83 mmol) was added by syringe and then cooled onan ice bath. POCl₃ (25 mL, 268 mmol) was added drop wise by syringe(over 20 minutes). The red solution was allowed to warm to roomtemperature (over 20 minutes), then the septum was removed, and themixture was treated with N-(4-chloro-3-methoxyphenyl)acetamide (5 g,25.05 mmol). The tube was sealed and the solution was stirred at 80° C.overnight. The solution was then pipetted onto ice, resulting information of a yellow precipitate. The precipitate was collected on aBuchner funnel, washed with water (1200 mL), and dried to provide 5.06 gof the title compound as a pale yellow solid. LCMS and ¹H NMR areconsistent with 2,6-dichloro-7-methoxyquinoline-3-carbaldehyde (5.06 g,19.76 mmol, 79% yield). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 10.33 (s, 1H),8.87 (s, 1H), 8.47 (s, 1H), 7.64 (s, 1H), 4.08 (s, 3H). LCMS (Method 1):m/z 256 [M+H]⁺.

Step-2: 6-chloro-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde

2,6-Dichloro-7-methoxyquinoline-3-carbaldehyde (5.06 g, 19.76 mmol) washeated at reflux in concentrated HCl (12M, 185 mL) overnight. Thematerial went into solution during heating and then a solid precipitatedduring the course of the reaction. The mixture was allowed to cool andthen was poured into water (1500 mL) resulting in further precipitation.The slurry was filtered on a Buchner funnel, washed with water (1500mL), and dried to provide 4.04 g of the title compound as ayellowish-brown solid. LCMS and ¹H NMR are consistent with6-chloro-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (4.04 g,17.00 mmol, 86% yield). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.22 (s, 1H),10.16-10.18 (m, 1H), 8.43 (s, 1H), 8.08 (s, 1H), 6.95 (s, 1H), 3.94 (s,3H). LCMS (Method 1): m/z 238 [M+H]⁺.

Step-3:N-((6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide

A mixture of6-chloro-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (2.00 g,8.42 mmol) and 2-methylpropane-2-sulfinamide (1.22 g, 10.07 mmol) wasplaced under an atmosphere of nitrogen. THF (20 mL) and titanium (IV)isopropoxide (Ti(O¹Pr)₄) (5.0 mL, 17.06 mmol) were added by syringe andthe resulting suspension was stirred at room temperature overnight. OnceLCMS indicated the reaction had gone to completion, the reaction wasquenched by drop wise addition of aqueous saturated NH₄Cl (10 mL). Themixture was triturated with EtOAc (450 mL), then filtered throughCelite® 545, and the Celite® was washed further with EtOAc (200 mL). Thefilter cake was then sonicated in EtOAc (450 mL) for 15 minutes, thenfiltered on a Buchner funnel. The two filtrates were combined, washedwith brine (200 mL), dried (Na₂SO₄), filtered, and evaporated underreduced pressure to provide 1.01 g of the title compound as a yellowsolid. LCMS and ¹H NMR are consistent with(E)-N-((6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(1.01 g, 2.96 mmol, 35.2% yield). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.21(s, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.08 (s, 1H), 6.97 (s, 1H), 3.94(s, 3H), 1.19 (s, 9H). LCMS (Method 1): m/z 341 [M+H]⁺.

Step-4:N-(1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

N-((6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(265 mg, 0.778 mmol) was placed in a 50 mL round-bottom flask under anatmosphere of nitrogen. DCM (7 mL) was added, and the suspension wascooled on a dry ice/chloroform bath (to approx. −60° C.).Methylmagnesium bromide (MeMgBr) (3M in ether, 0.80 mL, 2.40 mmol) wasadded drop wise. The reaction mixture was stirred at −60° C. for severalhours, then allowed to warm to room temperature overnight, resulting inan orange solution. Once LCMS indicated the reaction had gone tocompletion, the suspension was cooled on an ice bath and treated dropwise with water (3 mL). The resulting mixture was diluted with water (75mL) and extracted with EtOAc (75 mL+20 mL). Silica gel was added and theEtOAc was evaporated under reduced pressure to provide a wet globularmass. Heptane and MeOH were added and the mixture was evaporated underreduced pressure to provide a powder. The material was purified bycolumn chromatography on a Biotage® MPLC chromatography system (elutedwith 0 to 4.2% MeOH in DCM) to yield the title compound as a blue-greenbrittle foam. LCMS and ¹H NMR are consistent withN-(1-(6-chloro-7-methoxy-2-oxo-1, 2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (152.7 mg, 0.428 mmol, 55% yield).LCMS (Method 1): m/z 357 [M+H]⁺.

Step-5: 3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-onehydrochloride (III-4)

A solution ofN-(1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (149.6 mg, 0.419 mmol) in MeOH (3.8 mL) was cooledon an ice bath and treated drop wise with 4M HCl in 1,4-dioxane (2.2mL). The reaction was stirred for 25 minutes, during which time a smallamount of precipitate formed. The solvents were evaporated under reducedpressure at room temperature. The residue was triturated with 10 mL ofethyl ether, then collected on a Hirsch funnel, and washed with moreethyl ether to provide 115.6 mg of the title compound as a pale greensolid. LCMS and ¹H NMR are consistent with3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-one hydrochlorideIII-4 (115.6 mg, 0.400 mmol, 95% yield). ¹H NMR (300 MHz, Methanol-d₄):δ ppm 7.95 (s, 1H), 7.77 (s, 1H), 6.97 (s, 1H), 4.51 (q, J=6.84 Hz, 1H),3.98 (s, 3H), 1.68 (d, J=7.04 Hz, 3H). LCMS (Method 1): m/z 253 [M+H]⁺.

Example 7 Intermediate III-5:(S)-3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-one

Step-1: N-(4-chloro-3-methoxyphenyl)acetamide

To a solution of 4-chloro-3-methoxyaniline (50 g, 317 mmol) and DIPEA(110 mL, 635 mmol) in CH₂Cl₂ (700 mL) was added acetic anhydride (36 mL,381 mmol) drop wise at 0° C. and the reaction mixture was stirred atroom temperature for 3 h. The reaction then was quenched with water (250mL) and the organic layer was separated. The aqueous layer was extractedwith CH₂Cl₂ (100 mL×3). The combined organic layers were dried (Na₂SO₄),concentrated and purified by flash chromatography with CH₂Cl₂/MeOH togive N-(4-chloro-3-methoxy phenyl)acetamide (71 g, quantitative yield)as a white solid.

Step-2: 2,6-Dichloro-7-methoxyquinoline-3-carbaldehyde

To POCl₃ (450 g, 274 mL, 2.95 mol) in a 2 L flask was added anhydrousDMF (83.5 g, 89 mL, 14 mol) drop wise. The reaction mixture was warmedup to room temperature and stirred for 20 min. After thatN-(4-chloro-3-methoxyphenyl)acetamide (65 g, 327 mmol) was added portionwise at room temperature and the mixture was heated to 90° C. overnight.The reaction mixture was then cooled to room temperature and carefullyquenched into aqueous NaHCO₃ solution. The precipitation obtained wasfiltered, washed with water (100 mL×3) and then dried in vacuum oven togive 60 g of title compound (73%).

Step-3: 6-Chloro-2,7-dimethoxyquinoline-3-carbaldehyde

To 2,6-dichloro-7-methoxyquinoline-3-carbaldehyde (40 g, 157 mmol) inMeOH (1 L) and THF (200 mL) was added NaOMe (16.9 g, 314 mmol) portionwise at room temperature. The reaction mixture was refluxed for 3 h.After cooling to room temperature, the reaction was quenched by additionof aqueous NH₄Cl solution (200 mL). The mixture was extracted with EtOAc(200 mL×3). The combined organic layers were dried (Na₂SO₄),concentrated and purified by flash chromatography with hexanes/EtOAc(3:1) to give the desired product (37.89 g, 96%) as a yellow solid.

Step-4: 1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethanol

To a solution of 6-chloro-2,7-dimethoxyquinoline-3-carbaldehyde (36.74g, 151 mmol) in THF (1 L) at −78° C. was added a solution of MeMgCl inTHF (3 M, 75.5 mL, 226 mmol) drop wise. The reaction was stirred at roomtemperature for 3 h and then quenched with aqueous NH₄Cl solution (250mL). The organic layer was separated and the aqueous layer was extractedwith EtOAc (100 mL×3). The combined organic layers were dried (Na₂SO₄),concentrated, and purified by silica gel chromatography withhexanes/EtOAc (3:1) to afford the title compound (38.06 g, 91%).

Step-5: 1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethanone

To 1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethanol (36.74 g, 137.6 mmol)in CH₂Cl₂ (1 L) at 0° C. was added DMP (70.0 g, 165.1 mmol) portionwise. The reaction was stirred at room temperature for 2 h, and then wasquenched with an aqueous solution of NaHCO₃ and Na₂S₂O₃. After stirringfor 15 min, both layers became clear. The organic layer was separatedand the aqueous layer was extracted with CH₂Cl₂ (100 mL×2). The combinedorganic layers were dried (Na₂SO₄), concentrated and purified by silicagel chromatography with hexanes/EtOAc (4:1) to afford the title compound(30.02 g, 80%) as a white solid.

Step-6:(R,E)-N-(1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide

To 1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethanone (30.07 g, 113.5 mmol)in THF/toluene (100 mL/1 L) at room temperature was added(R)-2-methylpropane-2-sulfinamide (27.5 g, 227 mmol,) and Ti(OiPr)₄ (97mL, 340.5 mmol,). The reaction was refluxed with a Dean-Stark apparatus.After the reaction was refluxed for 4 h and 300 mL of solvent wasremoved, the reaction was cooled to room temperature. The solvent wasremoved under vacuum, and 200 mL of EtOAc was added to the residue,followed by 100 mL of saturated aqueous NaHCO₃ solution. After stirringfor 10 min, the reaction mixture was passed through a pad of celite. Thefiltrate was extracted with EtOAc (200 mL×2), dried (Na₂SO₄),concentrated and purified by silica gel chromatography withhexanes/EtOAc (1:1) to give the title compound (34.28 g, 82%).

Step-7:(R)—N—((S)-1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To(R,E)-N-(1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide(34.28 g, 93.15 mmol) in THF (600 mL) at −78° C., was added 1 ML-selectride (121 mL, 121 mmol) in THF drop wise. The reaction mixturewas warmed to room temperature and stirred for 3 h. The reaction wasquenched with aqueous saturated NH₄Cl (300 mL) solution and thenextracted with EtOAc (200 mL×2). The combined organic layers were dried(Na₂SO₄), concentrated and purified by silica gel chromatography withhexanes/EtOAc (1:1) to afford the title compound (29.27 g, 85%).

Step-8: (S)-3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1)-onehydrochloride salt (III-5)

To(R)—N—((S)-1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(30.35 g, 82 mmol) in dioxane (250 mL) was added 2 N HCl (250 mL) at rt.The reaction mixture was refluxed for 3 h, cooled to room temperatureand the solvent was removed under vacuum. The crude residue obtained wasdried under vacuum to give a crude product, which was further purifiedby trituration (CH₂Cl₂/MeOH/hexane) to obtain pure title compound III-5(17.65 g, 75%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.18 (s,1H), 8.24 (br, s, 3H), 7.99 (s, 1H), 7.86 (s, 1H), 7.02 (s, 1H), 4.41(m, 1H), 3.91 (s, 3H), 1.52 (d, J=6.87 Hz, 3H). LCMS (Method 3): Rt 3.48min, m/z 253.1 [M+H]⁺.

Example 8 Intermediate III-6:(R)-3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-one

The title compound III-6 was prepared in the same procedure describedfor III-5, except using (S)-2-methylpropane-2-sulfinamide in Step-6(Scheme-3). ¹H NMR (300 MHz, Methanol-d₄): δ ppm 7.92 (s, 1H), 7.75 (s,1H), 6.95 (s, 1H), 4.48 (q, J=6.84 Hz, 1H), 3.96 (s, 3H), 1.65 (d,J=6.74 Hz, 3H). LCMS: m/z 253 [M+H]⁺.

Example 9 Intermediate III-7:(S)-3-(1-aminoethyl)-6-chloro-7-(pyridin-2-ylmethoxy) quinolin-2(1H)-one

Step-1: 4-Chloro-3-(pyridin-2-ylmethoxy)aniline

To a mixture of 5-amino-2-chlorophenol (10 g, 69.63 mmol),pyridin-2-ylmethanol (7.98 g, 73.13 mmol) and triphenylphosphine (21.5g, 82.07 mmol) in THF (1.1 L) was added slowly diethylazadicarboxylate(DEAD) (13 mL, 82.07 mmol) at room temperature. The resulting mixturewas stirred at room temperature for 24 hours. Upon completion ofreaction, SiO₂ was added and solvents were evaporated to dryness. Thecrude product was purified by SiO₂ column chromatography eluted with0-100% EtOAc-hexanes and then with 2% MeOH in EtOAc to afford the titlecompound (11.8 g, 72%) as an off-white solid. Note: The ¹H NMR showed asmall amount of triphenylphosphine oxide impurity. This material wasused in the next step without further purification.

Step-2: N-(4-Chloro-3-(pyridin-2-ylmethoxy)phenyl)acetamide

To a mixture of 4-chloro-3-(pyridin-2-ylmethoxy)aniline (11.8 g, 50.27mmol) and diisopropylethylamine (DIEA) (9.93 mL, 57.81 mmol) in ethylacetate (250 mL) was added acetic anhydride (Ac₂O) (5.22 mL, 55.3 mmol).The resultant mixture was stirred overnight at ambient temperature. Themixture was diluted with EtOAc (1 L), and washed with water (200 mL).The organic layer was dried over anhydrous Na₂SO₄, filtered, andevaporated to dryness. The resulting residue was triturated withhexanes-dichloromethane to afford the title compound as white solid(11.62 g, 84% yield).

Step-3: 2,6-Dichloro-7-(pyridin-2-ylmethoxy)quinoline-3-carbaldehyde

Dimethylformamide (4 mL, 51.6 mmol) was placed in a 150 mL sealed tubeand cooled to 0° C. To the DMF was added phosphorous oxychloride (POCl₃)(15.6 mL, 168 mmol) drop wise over 30-40 minutes. The resulting mixturewas warmed to room temperature andN-(4-chloro-3-(pyridin-2-ylmethoxy)phenyl)acetamide (4.34 g, 15.68 mmol)was added. The reaction mixture was heated at 80° C. overnight. Themixture was then cooled to room temperature and carefully quenched withice. The solution turned red and a yellow precipitate was formed,filtered, washed with water and dried over P₂O₅ overnight to afford thetitle compound as yellow solid (3.53 g, 68% yield).

Step-4: 1-(2,6-Dichloro-7-(pyridin-2-ylmethoxy)quinolin-3-yl)ethanone

To a solution of2,6-dichloro-7-(pyridin-2-ylmethoxy)quinoline-3-carbaldehyde (1.0 g, 3.0mmol) in CH₂Cl₂ (40 mL) was added drop wise methyl magnesium bromide(MeMgBr) (3 M solution in diethyl ether, 1.5 mL, 4.50 mmol) at 0° C. Theresulting mixture was then stirred at ambient temperature for 1.5 hours.Upon completion of reaction, the mixture was slowly quenched with water(3 mL) and extracted with CH₂Cl₂ (50 mL). The organic layer wasseparated and dried over anhydrous Na₂SO₄. The solvents were evaporatedto dryness. The resulting residue was dissolved in CH₂Cl₂ (25 mL) andtreated with Dess-Martin Periodinate (2.54 g, 6.00 mmol). The mixturewas stirred at ambient temperature overnight. The mixture was thenquenched with an aqueous co-solution of 20% NaHCO₃ and 20% Na₂S₂O₃ (10mL) and stirred for 5 minutes at room temperature. The solution wasextracted with CH₂Cl₂ (40 mL), dried over anhydrous Na₂SO₄, filtered andevaporated. The resulting residue was purified by column chromatographyon an ISCO® chromatography system (SiO₂ column: eluted with CH₂Cl₂/MeOH0 to 10%) to afford the title compound (800 mg, 79%).

Step-5:(R,E)-N-(1-(2,6-dichloro-7-(pyridin-2-ylmethoxy)quinolin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide

To a mixture of1-(2,6-dichloro-7-(pyridin-2-ylmethoxy)quinolin-3-yl)ethanone (2.18 g,6.56 mmol) and (R)-2-methylpropane-2-sulfinamide (1.19 g, 9.84 mmol) inTHF:Toluene (40 mL:180 mL), was added titanium (IV) isopropoxide(Ti(O^(i)Pr)₄) (3.96 mL, 13.30 mmol). The resulting mixture was refluxedwith a Dean-Stark apparatus for 7 hours. The mixture was then cooled toroom temperature, quenched with water, and diluted with EtOAc (300 mL).The organic layer was washed with water (100 mL), dried over anhydrousNa₂SO₄, filtered and evaporated to dryness. The resulting residue waspurified by column chromatography on an ISCO® chromatography system(SiO₂ column: eluted with Hex/EtOAc 0 to 100%) to afford the titlecompound as yellow solid (1.4 g, 50% yield). The starting materialketone was also recovered (250 mg, 11% yield).

Step-6:(R)—N—((S)-1-(2,6-dichloro-7-(pyridin-2-ylethoxy)quinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R,E)-N-(1-(2,6-dichloro-7-(pyridin-2-ylmethoxy)quinolin-3-yl)ethylidene)-2-methyl propane-2-sulfinamide (900 mg, 1.99 mmol) in THF(25 mL) at −40 to −50° C. was added L-selectride (1M in THF, 1.98 mL,2.59 mmol) drop wise. The resulting mixture was stirred at −40 to −50°C. for 2 hours. Upon completion of reaction, the mixture was quenchedwith ice at −50° C., extracted with EtOAc (100 mL), dried, andevaporated. The resulting residue was purified by column chromatographyon an ISCO® chromatography system (SiO₂ column: Hex/EtOAc 0 to 100%)followed by trituration with hexanes-methylene chloride to afford thetitle compound (266 mg, 30% yield).

Step-7:(S)-3-(1-Aminoethyl)-6-chloro-7-(pyridin-2-ylmethoxy)quinolin-2(1H)-oneTFA salt (III-7)

To a mixture of(R)—N—((S)-1-(2,6-dichloro-7-(pyridin-2-ylmethoxy)quinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(1.1 g, 2.43 mmol) in 1,4-dioxane (6.6 mL), was added aqueous 1N HCl(6.6 mL) at room temperature. The resulting mixture was heated to 120°C. overnight. After TLC and MS showed completion of reaction, thesolvents were removed on a rotary evaporator and lyophilized to provideyellow solid. The crude solid was purified by reverse phasechromatography on an ISCO® chromatography system (C18 column: elutedwith H₂O/MeCN/0.1% CF₃CO₂H 0 to 100%) and the fractions were monitoredby LCMS. The pure fractions were combined and lyophilized to afford thetitle compound III-7 (920 mg, 86% yield) as the TFA salt. ¹H NMR (300MHz, DMSO-d₆): δ 12.17 (br s, 1H), 8.62 (d, J=4.95 Hz, 1H), 8.09 (br s,2H), 7.96-7.85 (m, 3H), 7.59 (d, J=7.9 Hz, 1H), 7.42-7.37 (m, 1H), 7.08(d, J=2.5 Hz, 1H), 5.33 (s, 2H), 4.39-4.38 (m, 1H), 1.51 (d, J=6.8 Hz,3H). LCMS (method 3): Rt 3.3 min, m/z 329.1 [M+H]⁺.

Example 10 Intermediate III-8:(S)-3-(1-aminoethyl)-6-chloro-1,8-naphthyridin-2(1H)-one

Step-1: 3-acetyl-6-chloro-1,8-naphthyridin-2(1H)-one

A mixture of 2-amino-5-chloronicotinaldehyde (1 g, 6.39 mmol) and2,2,6-trimethyl-4H-1,3-dioxin-4-one (1.362 g, 9.58 mmol) in xylenes (10mL) was heated to reflux for 3 hours, then cooled to room temperature,filtered, and washed with xylenes twice to afford 914 mg of3-acetyl-6-chloro-1,8-naphthyridin-2(1H)-one (64.3% yield). ¹H NMR (300MHz, DMSO-d₆): δ 12.68 (br, 1H), 8.63 (s, 1H), 8.49 (s, 1H), 8.39 (s,1H), 2.48 (s, 3H). LCMS (Method 1): Rt 1.60 min, m/z 223.03[M+H]⁺.

Step-2:(S)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

A mixture of tetraethoxytitanium (512 mg, 2.25 mmol),(R)-2-methylpropane-2-sulfinamide (163 mg, 1.35 mmol) and3-acetyl-6-chloro-1,8-naphthyridin-2(1H)-one (200 mg, 0.898 mmol) in THF(15 mL) was heated to 80° C. overnight, then cooled to room temperature.To this mixture was added NaBH₄ (170 mg, 4.49 mmol) and the mixture wasslowly warmed up to room temperature overnight. MeOH was then added toquench any excess NaBH₄, followed by the addition of water. The mixturewas filtered to remove solids, then extracted with EtOAc twice, driedover Na₂SO₄, and concentrated. The residue was purified on a Biotage®chromatography system using a 25 g SiO₂ column eluted on a gradient(first 20% to 100% EtOAc/Hexanes, then 0-5% MeOH/DCM) to afford(S)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(123 mg, 42% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.40 (s, 1H), 7.74 (s,1H), 7.75 (s, 1H), 7.24 (s, 1H), 5.24 (d, J=9.45 Hz, 1H), 4.42 (m, 3H),1.54 (d, J=6.93 Hz, 3H), 1.20 (s, 9H). LCMS (Method 1): Rt 2.07 min, m/z328.98 [M+H]⁺.

Step-3: (S)-3-(1-aminoethyl)-6-chloro-1,8-naphthyridin-2(1H)-one (III-8)

To a solution of((S)—N—((S)-1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(123 mg, 0.375 mmol) in MeOH (5 mL) was added HCl (2 mL, 8.00 mmol, 4Min 1,4-dioxane). The mixture was then stirred at room temperatureovernight. To this mixture was added 6 mL of ethyl ether and theresulting precipitate was filtered, washed with ethyl ether (2×), driedand concentrated to afford(S)-3-(1-aminoethyl)-6-chloro-1,8-naphthyridin-2(H)-one, HCl (96 mg, 98%yield). ¹H NMR (300 MHz, DMSO-d₆): δ 12.75 (br s, 1H), 8.60-8.35 (s,1H), 8.26 (br, 1H) 8.07 (s, 1H), 4.40-4.50 (m, 1H), 1.51 (d, J=6.78 Hz,3H). LCMS (Method 1): Rt 0.87 min, m/z 224.99 [M+H]⁺.

Example 11 Intermediate III-9:(S)-3-(1-Aminoethyl)-6-chloro-8-fluoroquinolin-2(1H)-one

Step-1: tert-Butyl (4-chloro-2-fluorophenyl)carbamate

A solution of 4-chloro-2-fluoroaniline (2 g, 13.74 mmol) anddi-tert-butyl dicarbonate (6.4 mL, 27.6 mmol) in 1,4-dioxane (50 mL) wasstirred at reflux for 2 days. The solvent was then evaporated. Theresulting oil was diluted with MeOH, water, and aqueous ammoniumhydroxide solution (10 mL each) and vigorously stirred for 45 minutes.The organic lower layer was separated. The organic material was dilutedwith EtOAc (50 mL), and washed with water (50 mL), 3.6% aqueous HClsolution (2×50 mL), saturated aqueous NaHCO₃ solution (50 mL), and thenagain with water (2×50 mL). The organic layer was dried (MgSO₄),filtered, and evaporated under reduced pressure to provide tert-butyl(4-chloro-2-fluorophenyl)carbamate (3.0011 g, 12.22 mmol, 89% yield) asa reddish liquid that solidified on standing. ¹H NMR (300 MHz, DMSO-d₆):δ ppm 9.12 (s, 1H), 7.63 (t, J=8.65 Hz, 1H), 7.42 (dd, J=10.85, 2.35 Hz,1H), 7.18-7.24 (m, 1H), 1.45 (s, 9H). LCMS (Method 1): m/z 246 [M+H]⁺.

Step-2: tert-Butyl (4-chloro-2-fluoro-6-formylphenyl)carbamate

An oven-dried 3-necked 500 mL round bottom flask was fitted with anoven-dried addition funnel and placed under an atmosphere of nitrogen.tert-Butyl (4-chloro-2-fluorophenyl)carbamate (5.44 g, 22.14 mmol) andethyl ether (91 mL) were added by syringe. The clear solution was cooledon an acetonitrile/dry ice bath (to approximately −40° C.).tert-Butyllithium (1.7M in pentane, 33 mL, 22.14 mmol) was added to theaddition funnel by cannula. The t-BuLi solution was added drop wise tothe ether solution (over ˜10 minutes), during which time the ethersolution began to turn orange. The solution was stirred at about −40° C.for 2 hours, during which time it progressively became more orange. DMF(8.7 mL, 112 mmol) was added drop wise (over ˜10 minutes), resulting inprecipitation of a yellow solid.

The MeCN/dry ice bath was replaced with an ice bath and the mixture wasstirred for an additional 2 hours. The reaction was then quenched bydrop wise addition of water (20 mL), resulting in a brown mixture andthe ice bath was removed. The mixture was diluted with EtOAc (100 mL),washed with water (2×100 mL), dried (Na₂SO₄), filtered, and evaporatedunder reduced pressure to provide 5.45 g of an oily black solid. Thematerial was triturated with hexanes (50 mL), collected on a Buchnerfunnel and washed with more hexanes to provide 2.73 g tert-butyl(4-chloro-2-fluoro-6-formylphenyl)carbamate as a yellow powder. Thefiltrate was evaporated under reduced pressure, the residue wastriturated in hexanes (˜15 mL), and the resulting yellow solid wascollected on a Hirsch funnel to provide a second crop of the titlecompound (0.66 g). A total of 3.39 g (12.4 mmol, 56% yield) oftert-butyl (4-chloro-2-fluoro-6-formylphenyl)carbamate was recovered. ¹HNMR (300 MHz, DMSO-d₆): δ ppm 9.93 (d, J=0.88 Hz, 1H), 9.47 (s, 1H),7.81-7.90 (m, 1H), 7.55-7.61 (m, 1H), 1.44 (s, 9H). LCMS (Method 1): m/z296 [M+Na].

Steps-3 & 4: (S)-3-(1-Aminoethyl)-6-chloro-8-fluoroquinolin-2(1H)-onehydrochloride (III-9)

An oven-dried 200 mL round bottom flask and stir bar were placed underan atmosphere of nitrogen. THF (17 mL) and diisopropylamine (1.59 mL,11.16 mmol) were added by syringe. The resulting solution was cooled ona dry ice/acetone bath (to approximately −78° C.) and thenn-butyllithium (1.6M in hexane, 7.1 mL, 11.36 mmol) was added drop wiseover a 5 minute period. After stirring for 15 minutes, a solution of(S)-ethyl 3-((tert-butoxycarbonyl)amino)butanoate K (860.7 mg, 3.72mmol) in THF (3.75 mL) was added drop wise over 5 minutes. The solutionwas stirred for 80 minutes at −78° C., and a solution of tert-butyl(4-chloro-2-fluoro-6-formylphenyl)carbamate (1016.4 mg, 3.71 mmol) inTHF (7.5 mL) was then added drop wise by syringe. The reaction wasstirred at −78° C. for another 22 minutes and then quenched by additionof saturated aqueous NH₄Cl solution (17 mL). The mixture was partitionedbetween EtOAc and water (100 mL each). The organic layer was dried(MgSO₄), filtered, and evaporated under reduced pressure to provide 1.88g of the title compound as an orange gum. The material was dissolved in1,4-dioxane (38 mL), treated with 12M aqueous HCl (0.96 mL), and stirredat 110° C. for 50 minutes. The sample was then allowed to cool. Thesolvent was evaporated under reduced pressure to provide 1.24 g of a redsolid. The material was triturated in IPA (25 mL), collected on a Hirschfunnel and washed sequentially with IPA (5 mL) and ethyl ether (˜20 mL)to provide (S)-3-(1-aminoethyl)-6-chloro-8-fluoroquinolin-2(1H)-onehydrochloride (370.4 mg, 1.337 mmol, 36% yield) as a red solid. ¹H NMR(300 MHz, DMSO-d₆): δ ppm 12.41 (s, 1H), 8.33 (br s, 3H), 8.10 (s, 1H),7.67-7.76 (m, 2H), 4.38-4.53 (m, 1H), 1.52 (d, J=7.04 Hz, 3H). LCMS(Method 1): m/z 241 [M+H]⁺.

Example 12 Intermediate V-1:7-chloro-1-methyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one

Step-1: Ethyl 2-chloro-4-(methylamino)pyrimidine-5-carboxylate

A solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (9.0 g, 40.5mmol, 1 eq.) in 75 ml MeOH was cooled to −20° C. and treated withmethylamine (33 wt % in EtOH, 5.1 ml, 40.5 mmol, 1 eq.) and TEA (7.9 g,81 mmol, 2 eq.). After stirring for 10 minutes, the reaction was pouredinto water and the resulting precipitate was collected and rinsed withwater.

Chromatography over 80 g silica gel with DCM as eluent followed bytrituration with Et₂O provided the title compound (5.16 g, 59%) as awhite solid.

Step-2: (2-Chloro-4-(methylamino)pyrimidin-5-yl)methanol (3)

In a dried 3-neck round bottom flask under N₂, a solution of ethyl2-chloro-4-(methylamino)pyrimidine-5-carboxylate (5.16 g, 23.9 mmol, 1eq.) in 240 ml THF was cooled to 0° C. LAH (1.8 g, 47.4 mmol, 2 eq.) wasadded portion-wise, followed by stirring at 0° C. After 60 min, 95 mL 5%aqueous NaOH was added drop wise, followed by addition of H₂O (50 ml).The mixture was extracted with EtOAc and dried over Na₂SO₄. The crudematerial was evaporated to dryness. The resulting solid was trituratedwith a mixture of DCM/EtOAc to provide the desired product (1.94 g, 46%)as a cream-colored solid. Chromatography of the mother liquor oversilica gel with EtOAc as eluent afforded an additional 0.84 g of theproduct (21%).

Step-3: 7-Chloro-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one (V-1)

In a dried 3-neck round bottom flask under N₂, a solution of(2-chloro-4-(methylamino)pyrimidin-5-yl)methanol (1.94 g, 11.1 mmol, 1eq.) in DMF (70 mL) was cooled to 0° C. NaH (60 wt % in oil, 445 mg,11.1 mmol, 1 eq.) was added portion-wise, followed by stirring at roomtemperature for 30 min. The reaction mixture was then cooled to −40° C.and CDI (1.90 g, 11.7 mmol, 1.05 eq.) was added portion-wise. After 4.5hours, 15 ml H₂O was added followed by extraction into EtOAc (3×). Thecombined extracts were washed with H₂O, then brine, and dried overNa₂SO₄. The crude extract was evaporated to dryness and the resultingsolid triturated with Et₂O. The unwanted solid was filtered off, and thefiltrate chromatographed over 30 g silica gel using a DCM to DCM:EtOAC(95/5) gradient to provide the title compound V-1 as a white solid (300mg, 13%). ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.22 (d, J=0.81, 1H), 5.27 (d,J=0.69, 1H), 3.47 (d, J=0.84, 1H). LC/MS (Method 3): Rt 3.78 min., m/z200 [M+H]⁺. Melting point: 143-146° C.

Example 13 Intermediate V-2:5-chloro-3-methyloxazolo[4,5-d]pyrimidin-2(3H)-one

Step-1: 2-chloro-4-(methylamino)pyrimidin-5-ol

To 2-chloro-5-methoxy-N-methylpyrimidn-4-amine (1.73 g, 10 mmol) inCH₂Cl₂ (100 mL) at −78° C. was added BBr₃ (3.76 g, 15 mmol) drop wise.The reaction mixture was then warmed up to room temperature and stirredovernight. The reaction mixture was then quenched with aqueous NaHCO₃solution (50 mL). The solvents were evaporated and the residue was driedunder vacuum. To the residue was added THF (50 mL) and the insolublesolid was filtered. The THF solution was concentrated and dried to givecrude compound, 2-chloro-4-(methylamino)pyrimidin-5-ol (1.30 g, 82%)which was used in the next step without further purification.

Step-2: 5-chloro-3-methyloxazolo[4,5-d]pyrimidin-2(3H)-one (V-2)

To 2-chloro-4-(methylamino)pyrimidin-5-ol (810 mg, 5.1 mmol) in THF (150mL) was added CDI (1.24 g, 7.64 mmol) and ^(i)Pr₂EtN (1 mL) at roomtemperature. The reaction was refluxed for 6 h. The mixture was thencooled to room temperature and the solvent was removed under vacuum. Tothe residue was added water (50 mL) and the mixture was extracted withCH₂Cl₂ (30 mL×3). The combined organic layers were dried (Na₂SO₄),concentrated and purified by ISCO using CH₂Cl₂ to CH₂Cl₂/MeOH (9:1) aseluent to afford the desired compound V-2 (690 mg, 73%). ¹H NMR (300MHz, DMSO-d₆) δ ppm: 8.22 (s, 1H), 3.49 (s, 3H). LCMS (Method 3): Rt3.65 min, m/z 186.0 [M+H]⁺.

TABLE 1 The Intermediates listed in Table 1 were either prepared usingthe methods described above or obtained from commercial sources.Intermediate No. Chemical names Structure II-1 6-chloro-2-oxo-1,2-dihydroquinoline-3- carbaldehyde

III-1 (S)-3-(1-aminoethyl)-6- chloroquinolin-2(1H)-one hydrochloride

III-2 (R)-3-(1-aminoethyl)-6- chloroquinolin-2(1H)-one hydrochloride

III-3 (S)-3-(1-aminoethyl)-6- chloro-7-fluoroquinolin- 2(1H)-one

III-4 3-(1-aminoethyl)-6-chloro-7- methoxyquinolin-2(1H)-one

III-5 (S)-3-(1-aminoethyl)-6- chloro-7-methoxyquinolin- 2(1H)-one

III-6 (R)-3-(1-aminoethyl)-6- chloro-7-methoxyquinolin- 2(1H)-one

III-7 (S)-3-(1-aminoethyl)-6- chloro-7-(pyridin-2-ylmethoxy)quinolin-2(1H)- one

III-8 (S)-3-(1-aminoethyl)-6- chloro-1,8-naphthyridin- 2(1H)-one

III-9 (S)-3-(1-aminoethyl)-6- chloro-8-fluoroquinolin- 2(1H)-one

V-1 7-chloro-1-methyl-1,4- dihydro-2H-pyrimido[4,5- d][1,3]oxazin-2-one

V-2 5-chloro-3-methyloxazolo[4,5- d]pyrimidin-2(3H)-one

Example 143-((benzo[d]oxazol-4-ylamino)methyl)-6-chloroquinolin-2(1H)-one (I-1)

Library Protocol A:

in a 1.5 mL vial was added benzo[d]oxazol-4-amine (158 μL, 0.032 mmol)in methanol, 6-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (150 μL,0.030 mmol) in methanol, and acetic acid (30 μL, 0.524 mmol) to give atan solution. The reaction was heated to 50° C. with shaking for 2hours. The volatiles were removed by vacuum 200 uL of toluene was addedthe reaction was shaken at room temperature for 15 minutes. Thevolatiles were removed by vacuum. 200 uL of DMA were added sodiumtriacetoxyborohydride (450 μL, 0.090 mmol) in DCE was added. Thereaction was shaken at room temperature for 4 hours. The volatiles wereremoved by vacuum. The residue was partitioned between 0.5 mL of 1N NaOHand 0.5 mL of a 3:1 mixture of EtOAc/ACN. The upper (organic) layer wasseparated and combined with a second extraction of the aqueous layerwith 0.5 mL of a 3:1 mixture of EtOAc/ACN. The volatiles were removedunder reduced pressure. The compound was purified using mass-triggeredHPLC to yield 1.3 mg (13% yield) of3-((benzo[d]oxazol-4-ylamino)methyl)-6-chloroquinolin-2(1H)-one. LCMS(method 4): Rt 1.71 min, m/z 326.1 [M+H]⁺.

Example 156-methoxy-3-(((2-methylbenzo[d]thiazol-5-yl)amino)methyl)quinolin-2(1H)-one(I-21)

Library Protocol B:

6-Methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (4.15 mg, 20 umol)was added as a solid to a 0.2 M solution of 4-aminobenzonitrile in DMA(165 uL, 33 umol). An additional volume of 1,2-dichoroethane (150 mL)was added, and the mixture was agitated at room temperature for 5minutes. The resultant mixture was charged with a 0.2 M suspension ofsodium triacetoxyborohydride in DCE (200 uL, 40 umol) and was agitatedovernight at room temperature. After LC-MS analysis confirmed thepresence of reductive amination product, the mixture was partitionedbetween ethyl acetate (500 uL) and saturated aqueous sodium bicarbonatesolution (500 uL). The organic layer was transferred, and the aqueouslayer was extracted once more with fresh ethyl acetate (500 uL). Theorganic layers were combined and concentrated under reduced pressurewith heat (50° C.). The crude residue was dissolved in DMSO (500 uL) andpurified by mass-triggered preparatory HPLC to yield the title compoundI-21 (1.8 mg, 25% yield). LC-MS (Method 4): Rt 1.18 min, m/z 352.14[M+H]⁺.

TABLE 2 The compounds listed in Table 1 were prepared using methodssimilar to the one described for the preparation of I-1 & I-21.

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

TABLE 3 LCMS signal and NMR chemical shifts of each compound listed inTable 2. Compounds LCMS^(a) Chemical Name I-1 m/z: 326.03 (M + H)+3-{[(1,3-benzoxazol-4-yl)amino]methyl}-6-chloro- Rt (min): 1.351,2-dihydroquinolin-2-one I-2 m/z: 355.89 (M + H)+6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3- Rt (min): 1.17benzoxazol-5-yl)amino]methyl}-1,2- dihydroquinolin-2-one I-3 m/z: 341.90(M + H)+ 6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5- Rt (min):1.09 yl)amino]methyl}-1,2-dihydroquinolin-2-one I-4 m/z: 352.90 (M + H)+6-chloro-3-{[(2-oxo-2H-chromen-6- Rt (min): 1.19yl)amino]methyl}-1,2-dihydroquinolin-2-one I-5 m/z: 367.95 (M + H)+6-chloro-3-{[(1-methyl-2-oxo-1,2,3,4- Rt (min): 1.12tetrahydroquinolin-6-yl)amino]methyl}-1,2- dihydroquinolin-2-one I-6m/z: 335.94 (M + H)+ 6-chloro-3-{[(isoquinolin-3-yl)amino]methyl}-1,2-Rt (min): 1.29 dihydroquinolin-2-one I-7 m/z: 360.06 (M + H)+4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3- Rt (min): 1.48yl)methyl]amino}naphthalene-1-carbonitrile I-8 m/z: 336.04 (M + H)+6-chloro-3-{[(quinolin-8-yl)amino]methyl}-1,2- Rt (min): 1.53dihydroquinolin-2-one I-9 m/z: 327.05 (M + H)+6-chloro-3-{[(2,3-dihydro-1-benzofuran-7- Rt (min): 1.45yl)amino]methyl}-1,2-dihydroquinolin-2-one I-10 m/z: 369.90 (M + H)+7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3- Rt (min): 1.19yl)methyl]amino}-4-methyl-3,4-dihydro-2H-1,4- benzoxazin-3-one I-11 m/z:355.92 (M + H)+ 7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3- Rt (min):1.02 yl)methyl]amino}-3,4-dihydro-2H-1,4-benzoxazin-3- one I-123-({[2-(1H-1,3-benzodiazol-5-yl)-1H-1,3-benzodiazol-5-yl]amino}methyl)-6,7-dimethoxy-1,2- dihydroquinolin-2-oneI-13 m/z: 339.96 (M + H)+ 6-chloro-3-{[(2-oxo-2,3-dihydro-1H-indol-6- Rt(min): 1.03 yl)amino]methyl}-1,2-dihydroquinolin-2-one I-14 m/z: 355.91(M + H)+ 6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3- Rt (min): 1.17benzoxazol-6-yl)amino]methyl}-1,2- dihydroquinolin-2-one I-15 m/z:336.02 (M + H)+ 6-chloro-3-{[(isoquinolin-8-yl)amino]methyl}-1,2- Rt(min): 0.87 dihydroquinolin-2-one I-16 m/z: 341.06 (M + H)+6-chloro-3-{[(3,4-dihydro-2H-1-benzopyran-8- Rt (min): 1.57yl)amino]methyl}-1,2-dihydroquinolin-2-one I-17 m/z: 383.91 (M + H)+6-chloro-3-{[(6-methoxy-2-oxo-1,2,3,4- Rt (min): 1.16tetrahydroquinolin-7-yl)amino]methyl}-1,2- dihydroquinolin-2-one I-18m/z: 353.96 (M + H)+ 6-chloro-3-{[(2-oxo-1,2,3,4-tetrahydroquinolin-7-Rt (min): 1.11 yl)amino]methyl}-1,2-dihydroquinolin-2-one I-19 m/z:338.93 (M + H)+ 6-chloro-3-{[(3-methyl-1H-indazol-6- Rt (min): 1.12yl)amino]methyl}-1,2-dihydroquinolin-2-one I-20 m/z: 353.93 (M + H)+6-chloro-3-{[(2-oxo-1,2,3,4-tetrahydroquinolin-6- Rt (min): 0.99yl)amino]methyl}-1,2-dihydroquinolin-2-one I-21 m/z: 352.14 (M + H)+6-methoxy-3-{[(2-methyl-1,3-benzothiazol-5- Rt (min): 1.18yl)amino]methyl}-1,2-dihydroquinolin-2-one I-22 m/z: 353.00 (M + H)+6-chloro-3-{[(5-oxo-5,6,7,8-tetrahydronaphthalen- Rt (min): 1.251-yl)amino]methyl}-1,2-dihydroquinolin-2-one I-23 m/z: 326.96 (M + H)+6-chloro-3-[({[1,2,4]triazolo[4,3-b]pyridazin-6- Rt (min): 0.85yl}amino)methyl]-1,2-dihydroquinolin-2-one I-24 m/z: 324.97 (M + H)+3-{[(1H-1,3-benzodiazol-5-yl)amino]methyl}-6- Rt (min): 0.81chloro-1,2-dihydroquinolin-2-one I-25 m/z: 325.10 (M + H)+6-chloro-3-{[(1H-indazol-6-yl)amino]methyl}-1,2- Rt (min): 1.12dihydroquinolin-2-one I-26 m/z: 342.10 (M + H)+3-{[(1,3-benzothiazol-6-yl)amino]methyl}-6-chloro- Rt (min): 1.231,2-dihydroquinolin-2-one I-27 m/z: 336.10 (M + H)+6-chloro-3-{[(quinolin-6-yl)amino]methyl}-1,2- Rt (min): 0.89dihydroquinolin-2-one I-28 m/z: 392.96 (M + H)+6-chloro-3-({[2-(trifluoromethyl)-1H-1,3- Rt (min): 1.22benzodiazol-5-yl]amino}methyl)-1,2- dihydroquinolin-2-one I-29 m/z:341.92 (M + H)+ 3-{[(1,3-benzothiazol-5-yl)amino]methyl}-6-chloro- Rt(min): 1.27 1,2-dihydroquinolin-2-one I-30 m/z: 339.16 (M + H)+3-{[(2,3-dihydro-1,4-benzodioxin-6- Rt (min): 1.08yl)amino]methyl}-6-methoxy-1,2-dihydroquinolin-2- one I-31 m/z: 319.19(M + H)+ 3-{[(1H-indazol-6-yl)amino]methyl}-6,7-dimethyl- Rt (min): 1.141,2-dihydroquinolin-2-one I-32 m/z: 350.16 (M + H)+6-chloro-3-{[(2-methylquinolin-6-yl)amino]methyl}- Rt (min): 0.911,2-dihydroquinolin-2-one I-33 m/z: 343.11 (M + H)+6-chloro-3-{[(2,3-dihydro-1,4-benzodioxin-6- Rt (min): 1.28yl)amino]methyl}-1,2-dihydroquinolin-2-one I-34 m/z: 321.14 (M + H)+3-{[(1H-indazol-6-yl)amino]methyl}-6-methoxy-1,2- Rt (min): 0.96dihydroquinolin-2-one I-35 m/z: 346.19 (M + H)+6-methoxy-3-{[(2-methylquinolin-6- Rt (min): 0.78yl)amino]methyl}-1,2-dihydroquinolin-2-one I-36 m/z: 338.14 (M + H)+3-{[(1,3-benzothiazol-6-yl)amino]methyl}-6- Rt (min): 1.06methoxy-1,2-dihydroquinolin-2-one I-37 m/z: 344.24 (M + H)+6,7-dimethyl-3-{[(2-methylquinolin-6- Rt (min): 0.94yl)amino]methyl}-1,2-dihydroquinolin-2-one I-38 m/z: 325.11 (M + H)+6-chloro-3-{[(1H-indazol-5-yl)amino]methyl}-1,2- Rt (min): 1.0dihydroquinolin-2-one I-39 m/z: 332.19 (M + H)+6-methoxy-3-{[(quinolin-6-yl)amino]methyl}-1,2- Rt (min): 0.76dihydroquinolin-2-one I-40 m/z: 336.15 (M + H)+3-{[(1,3-benzothiazol-6-yl)amino]methyl}-6,7- Rt (min): 1.25dimethyl-1,2-dihydroquinolin-2-one I-41 m/z: 347.25 (M + H)+6-tert-butyl-3-{[(1H-indazol-5-yl)amino]methyl}-1,2- Rt (min): 1.05dihydroquinolin-2-one ^(a)LCMS data are determined by Method 4.

Example 16(S)-3-(1-(1-acetyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-4-ylamino)ethyl)-6-chloroquinolin-2(1H)-one(I-42)

Step-1: 1-(4-chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)ethanone

A stirred suspension of 4-chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridinehydrochloride (349.7 mg, 1.830 mmol) in DCM (10 ml) was treated withDIEA (0.69 mL, 3.95 mmol), upon which the material went into solution.The solution was treated with acetyl chloride (0.15 mL, 2.11 mmol) andstirred at ambient temperature overnight. LCMS showed the reaction hadgone to completion. The solution was diluted with EtOAc (40 mL), washedwith brine and water (40 mL each), dried (Na₂SO₄), filtered, andevaporated under reduced pressure to provide1-(4-chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)ethanone (319.7mg, 1.626 mmol, 89% yield) as an off-white solid. ¹H NMR (300 MHz,DMSO-d₆): δ ppm 8.15 (d, J=5.28 Hz, 1H), 7.85 (br d, J=4.69 Hz, 1H),4.18 (br t, J=8.35 Hz, 2H), 3.15 (br t, J=8.50 Hz, 2H), 2.19 (s, 3H).LCMS (Method 1): Rt 1.63 min., m/z 197.02 [M+H]⁺.

Step-2:(S)-3-(1-(1-acetyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-4-ylamino)ethyl)-6-chloroquinolin-2(1H)-one (I-42)

A suspension of (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride III-1 (59.8 mg, 0.231 mmol),1-(4-chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)ethanone (29.3 mg,0.149 mmol), and zinc chloride (20.9 mg, 0.153 mmol) in cyclohexanol(321 μL, 3.04 mmol) was treated with DIEA (0.11 mL, 0.630 mmol) andstirred at 125° C. for six days. The sample was diluted with MeOH andDCM, treated with silica gel, and evaporated under reduced pressure. Thesample was chromatographed by Biotage MPLC (10 g silica gel column) with0 to 10% MeOH in DCM, with isocratic elution at 4.4% MeOH while peakseluted to provide(S)-3-(1-(1-acetyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-4-ylamino)ethyl)-6-chloroquinolin-2(1H)-oneI-42 (3.3 mg, 8.62 μmol, 3.74% yield). LCMS (Method 1): Rt 1.85 min.,m/z 382.99 [M+H]⁺.

Example 17(S)-6-chloro-3-(1-(1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-4-ylamino)ethyl)quinolin-2(1H)-one(I-43)

Step-1:4-chloro-1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine

A stirred suspension of 4-chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridinehydrochloride (299.8 mg, 1.569 mmol) in DCM (8.5 ml) was treated withDIEA (0.59 mL, 3.38 mmol), upon which the material went into solution.The solution was treated with MsCl (0.14 mL, 1.797 mmol) and stirred atambient temperature overnight. LCMS showed the reaction had gone tocompletion. The solution was diluted with EtOAc (40 mL), washed withbrine and water (40 mL each), dried (Na₂SO₄), filtered, and evaporatedunder reduced pressure to provide4-chloro-1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (307.2mg, 1.320 mmol, 84% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆):δ ppm 8.18 (d, J=5.57 Hz, 1H), 7.19 (d, J=5.28 Hz, 1H), 4.06 (t, J=8.79Hz, 2H), 3.08-3.22 (m, 5H). LCMS (Method 1): Rt 1.70 min., m/z 232.99[M+H]⁺.

Step-2:(S)-6-chloro-3-(1-(1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-4-ylamino)ethyl)quinolin-2(1H)-one (I-43)

A mixture of (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride III-1 (60.7 mg, 0.234 mmol),4-chloro-1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (34.0mg, 0.146 mmol), and zinc chloride (25.8 mg, 0.189 mmol) was placedunder nitrogen in a 2-dram vial. Cyclohexanol (0.32 mL, 3.03 mmol) andDIEA (0.11 mL, 0.630 mmol) were added by syringe and the mixture wasstirred at 125° C. five days. The sample was diluted with MeOH and DCM,treated with silica gel, and evaporated under reduced pressure. Thesample was chromatographed by Biotage MPLC (10 g silica gel column) with0 to 10% MeOH in DCM, with isocratic elution at 4% MeOH to provideimpure(S)-6-chloro-3-(1-(1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-4-ylamino)ethyl)quinolin-2(1H)-one(8.3 mg, 0.020 mmol, 8.46% yield). LCMS (Method 1): Rt 1.94 min., m/z418.90 [M+H]⁺.

Example 18(S)-3-(1-(1-acetyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-5-ylamino)ethyl)-6-chloroquinolin-2(1H)-one(I-44)

Step-1:1-(5-chloro-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)ethanone

A solution of 5-chloro-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (0.50 g,2.93 mmol) in DCM (15 ml) was treated with DIEA (1.05 ml, 6.01 mmol) andacetyl chloride (0.42 ml, 5.91 mmol) and stirred at ambient temperatureovernight. LCMS indicated the reaction had gone cleanly to completion.The solution was diluted with EtOAc (50 mL), washed with brine and water(50 mL each), dried (Na₂SO₄), filtered, and evaporated under reducedpressure to provide1-(5-chloro-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)ethanone (529.4mg, 2.490 mmol, 85% yield) as a light yellow solid, pure enough for useas is. 1H NMR (300 MHz, DMSO-d₆): δ ppm 8.04 (br s, 1H), 7.85 (d, J=5.57Hz, 1H), 4.35-4.47 (m, 2H), 3.88-3.98 (m, 2H), 2.31 (s, 3H). LCMS(Method 1): Rt 1.52 min., m/z+212.99 [M+H]⁺.

Step-2:(S)-3-(1-(1-acetyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-5-ylamino)ethyl)-6-chloroquinolin-2(1H)-one(I-44)

A 40 mL vial was charged with(S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride III-1(50.0 mg, 0.193 mmol), copper(I) iodide (68.6 mg, 0.360 mmol),1-(5-chloro-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)ethanone (69.9mg, 0.329 mmol), and tripotassium phosphate (342.5 mg, 1.614 mmol) andplaced under nitrogen. Dioxane (5.5 ml) and trans-1,2-diaminocyclohexane(0.04 mL, 0.333 mmol) were added by syringe and the mixture was stirredat 100° C. for 24 h. The sample was diluted with MeOH, treated withsilica gel, and evaporated under reduced pressure. The material waschromatographed by Biotage MPLC (10 g silica gel cartridge) with 0 to100% EtOAc in hexanes followed by with 10% MeOH in EtOAc to provide veryimpure(S)-3-(1-(1-acetyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-5-ylamino)ethyl)-6-chloroquinolin-2(1H)-one(15.9 mg, 0.040 mmol, 20.66% yield). LCMS (Method 1): Rt 1.83 min., m/z398.92 [M+H]⁺. The material was registered in CORE and sent to Branfordfor further purification; was not returned to WTN, no NMR.

Example 19(S)-3-(1-(1-acetyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-4-ylamino)ethyl)-6-chloroquinolin-2(1H)-one(I-46)

Step-1: Ethyl 2-chloro-4-(isobutylamino)pyrimidine-5-carboxylate

A solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (1.65 g, 7.5mmol, 1 eq.) in 45 mL DCM/THF (70/30) was cooled to −78° C. and treatedwith i-butylamine (552 mg, 7.5 mmol, 1 eq.) and TEA (1.5 g, 15 mmol, 2eq.). After 80 minutes, the reaction was poured into water and extractedwith DCM (×2). The combined extracts were washed with saturated aqueousNaHCO₃, dried over Na₂SO₄ and evaporated to provide 1.79 g of crudeproduct. Chromatography over 60 g silica gel with DCM/EtOAc (99/1) aseluent afforded 1.05 g title compound (53%) as white waxy solid.

Step-1: (2-Chloro-4-(isobutylamino)pyrimidin-5-yl)methanol

In a dried 3-neck round bottom flask under N₂, a solution of ethyl2-chloro-4-(isobutylamino)pyrimidine-5-carboxylate (1.30 g, 5 mmol, 1eq.) in 50 mL THF was cooled to 0° C. LAH (0.39 g, 10.2 mmol, 2 eq.) wasadded portion-wise, followed by stirring at 0° C. After 70 min., 20 mL5% aqueous NaOH was added drop wise, followed by 45 mL H₂O. Thegelatinous mix was filtered through celite and the filtrate extractedwith EtOAc (×2). The crude material was passed over a 20 g silica gelplug, eluting with hexane/EtOAc (75/25), to provide the desired product(0.60 g, 55%) as a pale yellow solid.

Step-2: 7-Chloro-1-isobutyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one

In a dried 3-neck round bottom flask under N₂, a solution of(2-chloro-4-(isobutylamino)pyrimidin-5-yl)methanol (180 mg, 0.83 mmol, 1eq.) in 11 mL DMF was cooled to 0° C. NaH (34 mg, 0.85 mmol, 1 eq.) wasadded portion-wise, followed by stirring at room temperature for 25 min.The reaction mixture was then cooled to −35° C. and CDI (141 mg, 0.87mmol, 1.05 eq.) was added portion-wise. After 40 min., H₂O (2 mL) wasadded followed by extraction into EtOAc (×2). The combined extracts werewashed with H₂O, brine, and dried over Na₂SO₄. Chromatography over 7.5 gsilica gel using a DCM/EtOAc gradient (0-20% EtOAc) as eluent affordedthe title compound (62 mg, 31%) as a white solid.

Step-4:(S)-7-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-isobutyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(I-46)

A mixture of 7-chloro-1-isobutyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(60 mg, 0.25 mmol, 1 eq.),(S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one III-1 free base (55 mg,0.25 mmol, 1 eq.) and DIPEA (37 mg, 0.29 mmol, 1.1 eq.) in 2 mL DMSO washeated in a sealed tube at 110° C. for 50 minutes. The reaction was thenpoured into water and extracted with EtOAc (×2). The combined extractswere washed with brine and dried over Na₂SO₄. The crude extract waschromatographed over 3.5 g silica gel eluting with an EtOAc toEtOAc/EtOH (98/2) gradient to afford I-46 (19 mg, 18%) as a white solid.¹H-NMR (300 MHz, CDCl₃, 50° C.) δ ppm: 10.5 (broad s, 0.8H), 7.90 (s,1H), 7.62 (s, 1H), 7.49 (s, 1H), 7.40 (d, J=7.98, 1H), 7.16 (d, J=8.52,1H), 6.00 (d, J=6.84, 1H), 5.27 (m, 1H), 5.06 (s, 2H), 3.82 (m, 2H),2.05 (m, 1H), 1.61 (d, J=6.87, 3H) 0.82 (m, 6H). LC/MS (Method 3): Rt4.6 min., m/z 428 [M+H]⁺.

Example 20(S)-7-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(I-47)

A mixture of ((S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride III-1 (243 mg, 0.94 mmol, 1.3 eq.),7-chloro-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one V-1 (144 mg,0.72 mmol, 1 eq.) and DIEA (260 mg, 2.0 mmol, 2.8 eq.) in 4 mL DMSO in asealed tube was heated at 110° C. for 1 hour. The reaction was thenpoured into water followed by extraction (2×) with EtOAc. Chromatographyover 10 g silica gel using an EtOAc to EtOAc:EtOH (98/2) gradientfollowed by trituration with Et₂O provided 60 mg of I-47 as a gold solid(21%). ¹H-NMR (300 MHz, CDCl₃): δ ppm 11.40 (broad s, 0.8H), 7.90 (s,1H), 7.67 (s, 1H), 7.50 (broad s, 1H), 7.40 (dd, J=2.19, 8.79, 1H), 7.27(m, 1H), 6.17 (d, J=8.49, 1H), 5.30 (m, 1H), 5.07 (s, 2H), 3.31 (s, 3H),1.62 (d, J=6.87, 3H). LC/MS (Method 3): Rt 4.0 min., m/z 386 [M+H]⁺.

Example 21(S)-7-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(I-48)

The title compound I 48 was prepared in the same procedure described forexample 19 by using amine III-7. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 11.78(br s, 1H), 8.61 (d, J=4.9 Hz, 1H), 7.98 (br s, 1H), 7.91-7.85 (m, 1H),7.79 (s, 1H), 7.75-7.62 (m, 2H), 7.56 (d, J=7.7 Hz, 1H), 7.39-7.35 (m,1H), 7.01 (s, 1H), 5.28 (s, 2H), 5.16-5.09 (m, 3H), 3.24-3.20 (m, 3H),1.38 (d, J=6.9 Hz, 3H). LCMS (Method-3): Rt 3.75 min, m/z 493.1[M+H]⁺.

Example 22(S)-7-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(I-49)

Step-1: Ethyl2-chloro-4-((4-methoxybenzyl)amino)pyrimidine-5-carboxylate

To an ice-cold solution of ethyl 2,4-dichloropyrimidine-5-carboxylate(10 g, 45.2 mmol) in anhydrous EtOH (100 mL) was added neat(4-methoxyphenyl)methanamine (7.68 mL, 58.8 mmol) and DIEA (16 mL, 91.0mmol). The reaction mixture was stirred at 0° C. for 2 h 30 min, thendiluted with EtOH and filtered. The filtrate cake was washed with EtOHand CH₂Cl₂. The filtrates were combined and concentrated. The crude wastriturated with Et₂O/MeOH to provide 2 g of the title compound. The restof material was purified by ISCO, using a gradient elution of EtOAc inCH₂Cl₂, to afford 6.5 g of the title compound. Total yield obtained was8.5 g, 59%.

Step-2: (2-chloro-4-((4-methoxybenzyl)amino)pyrimidin-5-yl)methanol

To an ice-cold solution of ethyl2-chloro-4-((4-methoxybenzyl)amino)pyrimidine-5-carboxylate (6.5 g, 20.2mmol) in 160 mL of THF was added LAH (20.2 mL, 40.4 mmol; 2M in THF)drop wise. After stirring at 0° C. for 2 h the reaction was quenched byslow addition of 25 mL of 0.5 M NaOH. The reaction mixture was dilutedwith CH₂Cl₂, stirred for 10 min and filtered through celite. The organicphase was dried over Na₂SO₄, filtered and concentrated to dryness underreduced pressure. The crude was purified by ISCO, using 120 gSiO₂-column with a gradient elution of EtOAc in CH₂Cl₂, providing 3.17 g(57% yield) of the title compound.

Step-3:7-chloro-1-(4-methoxybenzyl)-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one

A mixture of (2-chloro-4-((4-methoxybenzyl)amino)pyrimidin-5-yl)methanol(3.17 g, 11.3 mmol) and CDI (2.39 g, 14.7 mmol) in THF (78 mL) wasstirred in a sealed tube at 45° C. over 3 days then concentrated andpurified by ISCO, using a gradient elution of EtOAc in CH₂Cl₂, providingthe title compound (2.07 g, 60% yield).

Step-4: 7-chloro-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one

To a solution of7-chloro-1-(4-methoxybenzyl)-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(2.07 g, 6.8 mmol) in CH₃CN (90 mL) and H₂O (45 mL) was added solid(NH₄)₂[Ce(NO₃)₆] and the reaction mixture was stirred at roomtemperature for 2 h 30 min. The reaction was quenched by addition of 11mL of 1N HCl at 0° C., and then diluted with CH₂Cl₂, stirred for 20 minand filtered through celite. The layers were separated. The pH of aq.layer was brought to 7-8 followed by second extraction with CH₂Cl₂/MeOHsolvent mixture (9:1). The organic layers were combined, filteredthrough SiO₂ pad, dried over Na₂SO₄, and concentrated to dryness underreduced pressure. Sequential trituration with CH₃C1/MeOH and CH₂Cl₂/MeOHprovided 1.07 g (85% yield) of the pure title compound.

Step-5:(S)-7-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(I-49)

A mixture containing 7-chloro-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(200 mg, 1.1 mmol), (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one HClIII-1 (360 mg, 1.4 mmol) and DIEA (0.48 mL, 2.8 mmol) in 3 mL ofanhydrous DMSO was stirred at 110° C. for 75 min in a sealed tube. Thereaction mixture was diluted with water and extracted several times withCH₂Cl₂ and CH₂Cl₂/MeOH solvent mixture. The combined organic layers weredried over Na₂SO₄ and concentrated to dryness under reduced pressure.The crude was twice purified by ISCO and then triturated withCH₂Cl₂/MeOH to afford the title compound I-49 (16 mg, 4% yield). ¹H NMR(300 MHz, DMSO-d6, 80° C.) δ ppm: 11.70 (br s 1H), 10.38 (br s, 1H),7.98 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.45 (dd, J₁=8.5 Hz,J₂=2.4 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.15 (br d, 1H), 5.15-5.25 (m,1H), 5.13 (s, 2H), 1.45 (d, J=6.6 Hz, 3H). LCMS (Method 3), Rt 3.78 min.m/z 372.1 [M+H]⁺.

Example 237-((1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one.(I-50, I-51, and I-52)

A mixture of 7-chloro-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-oneV-1 (53.0 mg, 0.266 mmol) and3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-one hydrochlorideIII-4 (69.9 mg, 0.242 mmol) was treated with DMSO (1.5 ml) and DIEA (126μL, 0.721 mmol). The solution was stirred at 110° C. four hours. Thesample was mixed with water (20 mL) and extracted with DCM (2×15 mL) andEtOAc (15 mL). Silica gel was added and the solvent was evaporated underreduced pressure. The material was chromatographed by Biotage MPLC (10 gsilica gel column) with 0 to 8% MeOH in DCM, with isocratic elution whenpeaks came off to provide7-((1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(I-50) (45.1 mg, 0.093 mmol, 38.7% yield, HPLC purity 86.2% at 220 nm)as a solid racemic mixture. 1H NMR (300 MHz, DMSO-d₆): δ ppm 11.81 (s,1H), 7.99 (br s, 1H), 7.62-7.80 (m, 3H), 6.94 (s, 1H), 5.07-5.21 (m,3H), 3.87 (s, 3H), 3.23 (br s, 3H), 1.38 (d, J=7.04 Hz, 3H). LCMS(Method 1): Rt 2.22 min., m/z+415.91 [M+H]⁺. Chiral separation of theracemic mixture was performed to provide two pure enantiomers.

Chiral HPLC Condition: Injection Volume: 5 uL Column: Repaired ODH

Size: 0.46*10 cm;5 umMobile phase: Hex:EtOH=70:30Flow: 1.0 ml/min

Detector: 254 nm Instrument: LC-09 Temperature: 25° C.

(R)-7-((1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(I-51): 12 mg obtained, Chiral HPLC: Rt: 8.051 min, ee: >99.9%. LCMS(Method 4): Rt 1.16 min., m/z 416.12 [M+H]⁺.(S)-7-((1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(I-52) Chiral HPLC: Rt: 8.05 min, ee: >99%. LCMS (Method 1): 18 mgobtained, Chiral HPLC: Rt: 10.10 min, ee: >98.7%. LCMS (Method 4): Rt1.16 min., m/z 416.12 [M+H]⁺.

Example 24(R)-7-((1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(I-53)

A mixture of 7-chloro-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-oneV-1 (51.4 mg, 0.258 mmol) and(R)-3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-one hydrochlorideIII-2 (70.2 mg, 0.253 mmol) was treated with DMSO (1.6 ml) and DIEA (132μL, 0.756 mmol). The solution was stirred at 110° C. for ninety minutes.The sample was mixed with water (20 mL) and extracted with DCM (2×15mL). The extracts were dried (Na₂SO₄) and filtered, silica gel wasadded, and the solvent was evaporated under reduced pressure. Thematerial was chromatographed by Biotage MPLC (10 g silica gel column)with 0 to 100% EtOAc in hexanes, with isocratic elution when peaks cameoff. The product fractions were washed with water (2×40 mL), then dried(Na₂SO₄), filtered, and evaporated. The material was dissolved with AcCN(0.8 mL) and water (0.4 mL), frozen on a dry ice/acetone bath, thenlyophilized to provide(R)-7-((1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(28.7 mg, 0.071 mmol, 28.1% yield, HPLC purity 86% at 220 nm) as a whitesolid. 1H NMR (300 MHz, DMSO-d₆): δ ppm 7.91-8.02 (m, 2H), 7.74 (br s,2H), 7.13-7.26 (m, 2H), 5.06-5.21 (m, 3H), 3.23 (br s, 3H), 1.39 (d,J=6.74 Hz, 3H). LCMS (Method 1): Rt 2.21 min., m/z 403.81 [M+H]⁺.

Example 25(S)-7-((1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl)amino)-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(I-54)

The mixture of DIEA (0.142 ml, 0.812 mmol),(S)-3-(1-aminoethyl)-6-chloro-1,8-naphthyridin-2(1H)-one III-8 (60.5 mg,0.271 mmol), and7-chloro-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one V-1 (54 mg,0.271 mmol) in DMSO (1 ml) was heated to 110° C. for 4 hours. EtOAc wasadded. The organic extract was washed with water (2×50 mL) and brine (50mL), dried (Na₂SO₄), filtered, and evaporated under reduced pressure.The biotage purification with 0-10% MeOH/DCM on a 25 g column to afford24.8 mg of(S)-7-((1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl)amino)-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one(23.7%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.39 (s, 1H), 8.46 (s, 1H),8.26 (s, 1H), 7.95 (s, 1H), 7.73 (s, 1H), 6.78 (s, 1H), 5.03-5.18 (m,3H), 3.40 (s, 3H),), 1.38 (d, J=7.04 Hz, 3H). LCMS (Method 1): Rt 1.88min, m/z 387.00 [M+H]⁺.

Example 26(S)-5-((1-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-3-isobutyloxazolo[4,5-d]pyrimidin-2(3H)-one(I-55)

Step-1: 2-Chloro-N-isobutyl-5-methoxypyrimidin-4-amine

A mixture of 2,4-dichloro-5-methoxypyrimidine (2.0 g, 11.2 mmol),2-methylpropan-1-amine (1.4 mL, 14.0 mmol) and N,N-diisopropylethylamine (5.8 mL, 33.5 mmol) in MeOH (25 mL) was stirredat room temperature for 3 days. TLC showed clean conversion. Thereaction mixture was concentrated to dryness, and the residue waspartitioned between EtOAc and water. The organic layer was dried overNa₂SO₄, filtered and concentrated, and the residue was purified by ISCO(SiO₂: hexanes/EtOAc 0 to 30%) to afford the title compound as paleyellow oil (2.47 g, quant.), ¹H NMR (300 MHz, CDCl₃): δ 7.48 (s, 1H),5.45 (bs, 1H), 3.86 (s, 3H), 3.30 (t, J=6.0 Hz, 2H), 1.89 (m, 1H), 0.96(d, J=6.6 Hz, 6H). m/z 216.1 [M+H]⁺.

Step-2:(S)-6-Chloro-3-(1-((4-(isobutylamino)-5-methoxypyrimidin-2-yl)amino)ethyl)quinolin-2(1H)-one

A mixture of 2-chloro-N-isobutyl-5-methoxypyrimidin-4-amine (500 mg,2.32 mmol), (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride III-1 (300 mg, 1.16 mmol) and diisopropylethylamine (0.60mL, 3.47 mmol) in 1-butanol (10 mL) was heated in microwave at 200° C.for 2 h. MS showed the product. The reaction mixture was diluted withEtOAc and water, separated and washed with water and brine. After dryingover sodium sulfate, the solution was concentrated and the residue waspurified by ISCO (SiO₂: dichloromethane/MeOH 0 to 10%) to give the titlecompound as brown foam (293 mg, 63%). ¹H NMR (300 MHz, CD₃OD): δ 7.79(s, 1H), 7.64 (d, J=2.2 Hz, 1H), 7.48 (dd, J=8.8 Hz, 2.2 Hz, 1H), 7.32(d, J=8.5 Hz, 1H), 7.24 (s, 1H), 5.17 (q, J=6.9 Hz, 1H), 3.79 (s, 3H),3.02 (dd, J=10.3 Hz, 7.7 Hz, 1H), 1.74-1.62 (m, 1H), 1.54 (d, J=6.9 Hz,3H), 1.03-0.88 (m, 1H), 0.77 (d, J=6.6 Hz, 3H), 0.72 (d, J=6.6 Hz, 3H).m/z=402.2, 404.2 [M+H]⁺.

Step-3:(S)-6-Chloro-3-(1-((5-hydroxy-4-(isobutylamino)pyrimidin-2-yl)amino)ethyl)quinolin-2(1H)-one

To a solution of(S)-6-chloro-3-(1-((4-(isobutylamino)-5-methoxypyrimidin-2-yl)amino)ethyl)quinolin-2(1H)-one(73 mg, 0.182 mmol) in dichloromethane (5 mL), BBr₃ (1.0 M indichloromethane, 2.7 mL, 2.7 mmol) was added slowly and the mixture wasstirred at room temperature for 3 days. MS analysis showed product. Thereaction mixture was cooled to 0° C. and MeOH was slowly added. Theresulting solution was stirred at room temperature for 30 min. Afterevaporation to dryness for 3 times, the title compound was obtained asbrown foam (150 mg). ¹H NMR (300 MHz, CD₃OD): δ 7.82 (s, 1H), 7.67 (d,J=2.2 Hz, 1H), 7.49 (dd, J=8.8 Hz, 2.2 Hz, 1H), 7.33 (d, J=9.0 Hz, 1H),7.03 (s, 1H), 5.19 (q, J=7.4 Hz, 1H), 3.11-3.01 (m, 1H), 1.76-1.64 (m,1H), 1.55 (d, J=6.9 Hz, 3H), 1.02 (d, J=0.8 Hz, 1H), 0.98-0.92 (m, 1H),0.78 (d, J=6.6 Hz, 3H), 0.72 (d, J=6.6 Hz, 3H). m/z 388.2, 390.2 [M+H]⁺.

Step-3:(S)-5-((1-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-3-isobutyloxazolo[4,5-d]pyrimidin-2(3H)-one

To a solution of(S)-6-chloro-3-(1-((5-hydroxy-4-(isobutylamino)pyrimidin-2-yl)amino)ethyl)quinolin-2(1H)-one(150 mg, 0.182 mmol) in dichloromethane (10 mL), CDI (59 mg, 0.364 mmol)was added and stirred at room temperature overnight. MS showed theproduct. The reaction mixture was concentrated to dryness, and theresidue was partitioned by water and EtOAc. The organic layer was washedwith water and brine, and then dried over sodium sulfate. Afterfiltration and concentration, the crude was purified by ISCO (SiO₂:Hexanes/EtOAc 0 to 100%) to give the title compound as glassy film (32mg, 42%). After lyophilization, the title compound I-55 was obtained aswhite solid (30 mg). ¹H NMR (300 MHz, CD₃OD): δ 7.92 (s, 1H), 7.77 (s,1H), 7.58 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.6 Hz, 2.2 Hz, 1H), 7.33 (d,J=8.8 Hz, 1H), 5.26 (q, J=6.9 Hz, 1H), 3.59-3.48 (m, 2H), 2.06 (bs, 1H),1.51 (d, J=6.9 Hz, 3H), 0.79 (bs, 6H). LCMS (Method 3): Rt 4.86 min, m/z414.1, 416.1 [M+H]⁺.

Example 27(S)-5-((1-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)oxazolo[4,5-d]pyrimidin-2(3H)-one(I-56)

Step-1:(S)-3-(1-((4-Amino-5-methoxypyrimidin-2-yl)amino)ethyl)-6-chloroquinolin-2(1H)-one

A mixture of 2-chloro-5-methoxypyrimidin-4-amine (370 mg, 2.32 mmol),(S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride III-1 (300mg, 1.16 mmol) and diisopropylethylamine (0.60 mL, 3.47 mmol) in1-butanol (8 mL) was heated in microwave at 200° C. for 2 h. MS showedthe product. The reaction mixture was diluted with EtOAc and water,separated and washed with water and brine. After drying over sodiumsulfate, the solution was concentrated and the residue was purified byISCO (SiO₂: hexanes/EtOAc 0 to 100% then dichloromethane/MeOH 0 to 20%)to give the title compound as brown solid (174 mg, 43%). ¹H NMR (300MHz, CD₃OD): δ 7.79 (s, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.8 Hz,2.2 Hz, 1H), 7.35 (s, 1H), 7.29 (d, J=8.8 Hz, 1H), 5.11 (q, J=6.9 Hz,1H), 3.73 (s, 3H), 1.48 (d, J=6.9 Hz, 3H). m/z=346.1, 348.1 [M+H]⁺.

Step-2:(S)-3-(1-((4-Amino-5-hydroxypyrimidin-2-yl)amino)ethyl)-6-chloroquinolin-2(1H)-one

To a solution of(S)-3-(1-((4-amino-5-methoxypyrimidin-2-yl)amino)ethyl)-6-chloroquinolin-2(1H)-one(90 mg, 0.26 mmol) in dichloromethane (5 mL), BBr₃ (1.0 M indichloromethane, 3.9 mL, 3.9 mmol) was added slowly and the mixture wasstirred at room temperature for 2 days. MS showed >90% conversion. Thereaction mixture was cooled to 0° C. and MeOH was slowly added. Theresulting solution was stirred at room temperature for 30 min. Afterevaporation to dryness for 3 times, the title compound 3 was obtained asbrown foam (100 mg). This was used in the next step without furtherpurification. ¹H NMR (300 MHz, CD₃OD): δ 7.88 (s, 1H), 7.71 (d, J=2.2Hz, 1H), 7.49 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.33 (d, J=8.7 Hz, 1H), 7.09(s, 1H), 5.22 (q, J=6.9 Hz, 1H), 1.56 (d, J=6.9 Hz, 3H). m/z 332.1,334.1 [M+H]⁺.

Step-3:(S)-5-((1-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)oxazolo[4,5-d]pyrimidin-2(3H)-one(I-56)

To a solution of(S)-3-(1-((4-amino-5-hydroxypyrimidin-2-yl)amino)ethyl)-6-chloroquinolin-2(1H)-one(100 mg, 0.26 mmol) in dichloromethane (5 mL) and DMF (2 mL), CDI (84mg, 0.52 mmol) was added and stirred at room temperature overnight. MSshowed the product. The reaction mixture was concentrated to dryness,and the residue was partitioned with water and EtOAc. The organic layerwas washed with water and brine, and then dried over sodium sulfate.After filtration and concentration, the crude was purified by ISCO(SiO₂: Hexanes/EtOAc 0 to 100%) to give the title compound as glass film(32 mg, 42%). After lyophilization, the desired product I-56 wasobtained as white solid (44 mg, 47%). ¹H NMR (300 MHz, CD₃OD): δ 7.81(s, 1H), 7.66 (s, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.45 (dd, J=8.8 Hz, 2.2Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 5.21 (q, J=6.9 Hz, 1H), 1.52 (d, J=6.8Hz, 3H). LCMS (Method 3): Rt 8.01 min, m/z 358.1, 360.1 [M+H]⁺.

Example 28(S)-5-((1-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-3-methyloxazolo[4,5-d]pyrimidin-2(3H)-one(I-57)

Step-1: 2-Chloro-5-methoxy-N-methylpyrimidin-4-amine

At 0° C., to a solution of 2,4-dichloro-5-methoxypyrimidine (5.2 g, 29.0mmol) in MeOH (50 mL), a solution of methylamine in EtOH (8 M, 8.3 mL,66.8 mmol) was added slowly, and then allowed the mixture to warm toroom temperature for 30 min. TLC showed completed reaction. The reactionmixture was concentrated to dryness, and the solid was dissolved indichloromethane and washed with saturated sodium bicarbonate. Theorganic layer was dried over magnesium sulfate and concentrated to givethe desired product as white solid (4.80 g, 95%). ¹H NMR (300 MHz,CDCl₃): δ 7.48 (s, 1H), 5.46 (bs, 1H), 3.85 (s, 3H), 3.04 (d, J=4.9 Hz,3H).

Step-2:(S)-6-Chloro-3-(1-((5-methoxy-4-(methylamino)pyrimidin-2-yl)amino)ethyl)quinolin-2(1H)-one

A mixture of 2-chloro-5-methoxy-N-methylpyrimidin-4-amine (603 mg, 3.47mmol), (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochlorideIII-1 (300 mg, 1.16 mmol) and diisopropylethylamine (0.60 mL, 3.47 mmol)in isopropanol (10 mL) was heated in microwave at 180° C. for 2.5 h. MSanalysis showed the product. The reaction mixture was diluted with EtOAcand water, separated and washed with water and brine. After drying oversodium sulfate, the solution was concentrated and the residue waspurified by ISCO (SiO₂: Hexanes/EtOAc 0 to 100%) to give the titlecompound as brown foam (110 mg, 26%). ¹H NMR (300 MHz, CDCl₃): δ 10.86(bs, 1H), 9.59 (bs, 1H), 7.82 (s, 1H), 7.56 (d, J=2.2 Hz, 1H), 7.42 (dd,J=8.8 Hz, 2.2 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.01 (m, 1H), 6.07 (m,1H), 5.46 (m, 1H), 3.73 (s, 3H), 2.99 (d, J=5.2 Hz, 3H), 1.60 (d, J=6.9Hz, 3H). m/z 360.1, 362.1 [M+H]⁺.

Step-3:(S)-6-Chloro-3-(1-((5-hydroxy-4-(methylamino)pyrimidin-2-yl)amino)ethyl)quinolin-2(1H)-one

To a solution of(S)-6-chloro-3-(1-((5-methoxy-4-(methylamino)pyrimidin-2-yl)amino)ethyl)quinolin-2(1H)-one(110 mg, 0.306 mmol) in dichloromethane (40 mL), BBr₃ (0.44 mL, 4.59mmol) was added and stirred at room temperature overnight. MS showed thepresence of product. The reaction mixture was cooled to 0° C. and MeOHwas slowly added. The resulting solution was stirred at room temperaturefor 30 min. After evaporation to dryness, the residue was diluted withwater and EtOAc, and the organic layer was separated and washed withbrine. After drying over sodium sulfate, the solution was concentratedto give the title compound 5 as yellow solid (87 mg, 82%), which wasused for the next step without further purification. ¹H NMR (300 MHz,CD₃OD): δ 7.88 (s, 1H), 7.69 (s, 1H), 7.50 (dd, J=8.8 Hz, 2.2 Hz, 1H),7.32 (d, J=8.6 Hz, 1H), 6.99 (s, 1H), 5.24 (m, 1H), 2.97 (s, 3H), 1.58(d, J=6.9 Hz, 3H). m/z 346.1, 348.1 [M+H]⁺.

Step-4:(S)-5-((1-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-3-methyloxazolo[4,5-d]pyrimidin-2(3H)-one(I-57)

To a solution of(S)-6-chloro-3-(1-((5-hydroxy-4-(methylamino)pyrimidin-2-yl)amino)ethyl)quinolin-2(1H)-one (87 mg, 0.25 mmol) in dichloromethane (30mL), CDI (45 mg, 0.28 mmol) was added and stirred at room temperatureovernight. MS showed the product. The reaction mixture was concentratedto dryness, and the residue was purified by ISCO (SiO₂: Hexanes/EtOAc 0to 100%) to give the desired product I-57 as brown foam (55 mg, 59%). ¹HNMR (300 MHz, CDCl₃): δ 10.94 (s, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.51(d, J=2.2 Hz, 1H), 7.50 (dd, J=8.8 Hz, 2.2 Hz, 1H), 6.05 (d, J=8.2 Hz,1H), 5.28 (m, 1H), 3.32 (s, 3H), 1.63 (d, J=6.9 Hz, 3H). LCMS (method3): Rt 4.19 min, m/z 372.1, 374.1 [M+H]⁺.

Example 29(S)-6-chloro-3-(1-((9-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)ethyl)quinolin-2(1H)-one(I-58)

Step-1: 2-chloro-N-methyl-5-nitropyrimidin-4-amine

To a solution of 2,4-dichloro-5-nitropyrimidine (1.0 g, 5.2 mmol) in THF(15 mL) at −78° C., was added MeNH₂ (5.1 mL, 2M in THF, 10.2 mmol) dropwise over a period of 20 minutes. The reaction mixture was stirred foranother 2.5 hours. It was then allowed to warm up to room temperatureslowly. The mixture was concentrated under reduced pressure and theresidue was partitioned between EtOAc and water. The organic layer wasseparated and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine, dried (Na₂SO₄) and concentratedin vacuum. The residue was purified on ISCO (40 g silica gel column,EtOAc/hexanes 0-20%) to give the title compound (0.78 g, 80%).

Step-2: 2-chloro-N⁴-methylpyrimidine-4,5-diamine

A mixture of 2-chloro-N-methyl-5-nitropyrimidin-4-amine (0.77 g, 4.1mmol) and SnCl₂.2H₂O (3.6 g, 16.3 mmol) in EtOH (45 mL) was heated to80° C. under N₂ and stirred for two hours. It was then concentratedunder reduced pressure. EtOAc and Celite were added to the residue andthe mixture was basified with saturated Na₂CO₃ (aq.) to pH 9-10. Themixture was filtered through a pad of Celite and washed with EtOAc. Theorganic layer was separated and washed with brine, dried (Na₂SO₄) andconcentrated in vacuum. The residue was purified on ISCO (12 g silicagel column, EtOAc/hexanes 0-100%) to give the title compound (0.43 g,66%).

Step-3: 2-chloro-9-methyl-7H-purin-8(9H)-one

To a solution of 2-chloro-N⁴-methylpyrimidine-4,5-diamine (150 mg, 0.95mmol) in anhydrous THF (20 mL) was added CDI (310 mg, 1.9 mmol) underN₂. The reaction mixture was stirred at room temperature overnight. Itwas concentrated in vacuum and the residue was purified on ISCO (20 gsilica gel column, MeOH/dichloromethane 0-10%) to afford the titlecompound (0.11 g, 63%).

Step-4(S)-6-chloro-3-(1-((9-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)ethyl)-quinolin-2(1H)-one(I-58)

A mixture of (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride III-1 (52 mg, 0.20 mmol),2-chloro-9-methyl-7H-purin-8(9H)-one (110 mg, 0.60 mmol) andN,N-diisopropylethylamine (150 L, 0.86 mmol) in n-BuOH (1.5 mL) washeated in the microwave at 200° C. for 3.5 hours. It was combined withanother batch and purified on ISCO (20 g silica gel column,EtOAc/hexanes 0˜100%) to afford the desired product I-58 as an off-whitesolid (33 mg, 22%). m.p. 104-106° C. ¹H NMR (300 MHz, DMSO-d₆) δ ppm:11.93 (s, 1H), 10.67 (s, 1H), 7.74 (s, 1H), 7.71 (d, J=2.5 Hz, 1H), 7.70(s, 1H), 7.46 (dd, J=8.8, 2.5 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.18 (d,J=7.7 Hz, 1H), 5.12 (m, 1H), 3.16 (s, 3H), 1.37 (d, J=6.9 Hz, 3H). LCMS(LCMS method 1, APCI): 98% pure @254 nm, Rt 3.87 min, m/z 371, 373[M+H]⁺.

Example 30(S)-6-Chloro-3-(1-((8-oxo-8,9-dihydro-7H-purin-2-yl)amino)ethyl)quinolin-2(1H)-one(I-59)

Step-1: 2-chloropyrimidine-4,5-diamine

A mixture of 2-chloro-5-nitropyrimidin-4-amine (1.0 g, 5.7 mmol) andSnCl₂.2H₂O (5.2 g, 22.9 mmol) in EtOH (55 mL) under N₂ was heated to 80°C. and stirred for two hours. The mixture was then concentrated underreduced pressure. EtOAc and Celite were added to the residue and themixture was basified with saturated Na₂CO₃ (aq.) to pH 9-10. The mixturewas filtered through a pad of Celite and washed with EtOAc. The organiclayer was separated and washed with brine, dried (Na₂SO₄) andconcentrated in vacuum. The residue was purified on ISCO (20 g silicagel column, EtOAc/hexanes 0-100%) to give the title compound (0.41 g,49%).

Step-2: 2-chloro-7H-purin-8(9H)-one

To a solution of 2-chloropyrimidine-4,5-diamine (200 mg, 1.38 mmol) inanhydrous THF (25 mL) was added CDI (225 mg, 1.38 mmol) under N₂. Thereaction mixture was stirred at room temperature overnight. It wasconcentrated in vacuum and the residue was purified on ISCO (12 g silicagel column, EtOAc/hexanes 0-100%). The solid obtained was a mixture ofthe desired product and imidazole. It was dissolved in DCM, washed with1N HCl (aq.) and water, dried (Na₂SO₄) and concentrated in vacuum toafford the title compound as a white solid (170 mg, 72%).

Step-3:(S)-6-chloro-3-(1-((8-oxo-8,9-dihydro-7H-purin-2-yl)amino)ethyl)quinolin-2(1H)one(I-59)

A mixture of (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride III-1 (52 mg, 0.20 mmol), 2-chloro-7H-purin-8(9H)-one (100mg, 0.60 mmol) and N,N-diisopropylethylamine (200 L, 1.15 mmol) inn-BuOH (1.5 mL) was heated in the microwave at 200° C. for three hours.It was purified on ISCO (12 g silica gel column, EtOAc/hexanes 0˜100%,then MeOH/DCM 0˜10%) to afford the desired product I-59 as a pale yellowsolid (20 mg, 19%). m.p. 138-140° C. ¹H NMR (300 MHz, DMSO-d₆) δ: 11.92(s, 1H), 11.27 (br.s, 1H), 10.40 (s, 1H), 7.71 (s, 1H), 7.70 (d, J=2.2Hz, 1H), 7.67 (s, 1H), 7.46 (dd, J=8.8, 2.2 Hz, 1H), 7.28 (d, J=8.8 Hz,1H), 7.02 (d, J=8.0 Hz, 1H), 5.07 (m, 1H), 1.36 (d, J=6.9 Hz, 3H). LCMS(method 3): 95% pure @254 nm, Rt 7.58 min, m/z 357, 359 [M+H]⁺.

Example 31(S)-6-Chloro-3-(1-((6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)ethyl)quinolin-2(1H)-one (I-60)

Step-1: 5,5-Dibromo-2-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

To a solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 2.6 mmol)in t-BuOH (25 mL) was added 90% Py.HBr₃ (2.77 g, 7.8 mmol) over theperiod of 30 min. and stirred for 3 h at room temperature. The reactionmixture was concentrated and dissolved in EtOAc (50 mL) and water (30mL). The EtOAc layer was separated and aqueous layer was extracted withEtOAc (30 mL). The combined extracts were washed with H₂O, brine, dried(Na₂SO₄) and concentrated to give crude5,5-dibromo-2-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (855 mg) whichwas used for the next step.

Step-2: 2-Chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

To a solution of5,5-dibromo-2-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (855 mg, 2.6mmol) in THF (20 mL), was added acetic acid (10 mL) at 0° C. andfollowed by Zn dust (683 mg, 10.45 mmol). The resultant mixture wasstirred at 0° C. for 5 min., then warmed to rt and stirred for 1 h. Thereaction mixture was filtered through a pad of celite and washed withEtOAc (50 mL). The filtrate was concentrated and purified by ISCO (SiO₂:DCM/MeOH 0 to 10%) to give the pure2-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (330 mg, 75%).

Step-2:(S)-6-Chloro-3-(1-((6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)ethyl)-quinolin-2(1H)-one(I-60)

To a mixture of 2-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (300 mg,1.15 mmol) and (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride III-1 (300 mg, 1.77 mmol) in EtOH (2 mL) was added DIEA(0.4 mL, 2.3 mmol). The resultant mixture was heated at 145° C. for 4.5h in a microwave. After TLC and MS showed completion of the reaction,the mixture was cooled to room temperature and diluted with EtOAc (20mL). The organic layer was washed with water (20 mL), brine, dried overanhydrous Na₂SO₄, filtered and evaporated to dryness. The resultingresidue was purified by reverse phase to give the title compound as awhite solid I-60 (50 mg, 12%). mp. 154-156° C. ¹H NMR (300 MHz, DMSO-d₆)δ 12.07 (brs, NH), 11.92 (brs, NH), 7.96 (brs, NH), 7.81 (m, 11H), 7.77(d, J=2.2 Hz, 1H), 7.53 (dd, J=2.2 Hz, 6.6 Hz, 1H), 7.33 (d, J=8.8 Hz,1H), 5.18 (m, 1H), 3.47 (s, 2H), 1.45 (d, J=6.6 Hz, 1H). LCMS: Rt 3.85min, m/z 356.1 [M+H]⁺.

Example 32(S)-6-Chloro-3-(1-((7-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)ethyl)-quinolin-2(1H)-one(I-61)

Step-1: 2-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 6.5mmol) in MeCN (25 mL) at 5° C. was added NaH (313 mg, 7.8 mmol). Theresultant mixture was brought to room temperature and stirred for 30min. Then MeI was added at 0° C. and continued stirring at roomtemperature for overnight. The reaction mixture was filtered through apad of celite and washed with MeCN (10 mL). The filtrate wasconcentrated and recrystallized from Et₂O. The mother liquor wasconcentrated and purified by ISCO (SiO₂: DCM/EtOAc 0 to 30%).Altogether, the recrystallized and purified provided the pure compound(835 mg, 77%).

Step-2:5,5-Dibromo-2-chloro-7-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

To a solution of 2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (835 mg,5 mmol) in t-BuOH/H₂O ((10 mL/3 mL) was added NBS (2.67 g, 15 mmol) andstirred for 3 h at room temperature. The reaction mixture wasconcentrated and dissolved in EtOAc (30 mL). The EtOAc layer was washedwith NaHCO₃, brine, dried (Na₂SO₄) and concentrated to give crude5,5-Dibromo-2-chloro-7-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (1.72g) which was used for the next step.

Step-3: 2-Chloro-7-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

To a solution of5,5-Dibromo-2-chloro-7-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (1.7g, 5 mmol) in THF (10 mL), was added acetic acid (20 mL) at 0° C. andfollowed by Zn dust (1.3 g, 20 mmol). The resultant mixture was stirredat 0° C. for 5 min., then warmed to room temperature and stirred for 1h. The reaction mixture was filtered through a pad of celite and washedwith EtOAc (50 mL). The filtrate was concentrated and recrystallizedfrom EtOH (414 mg). The mother liquor was concentrated and purified byISCO (SiO₂: DCM/MeOH 0 to 10%). Altogether, the recrystallized andpurified provided the pure title compound (573 mg, 62%).

Step-4:(S)-6-Chloro-3-(1-((7-methyl-6-oxo-6,7-dihydro-H-pyrrolo[2,3-d]pyrimidin-2-yl)-amino)ethyl)-quinolin-2(1H)-one(I-61)

To a mixture of 2-chloro-7-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one(212 mg, 1.16 mmol) and (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride III-1 (200 mg, 0.77 mmol) in EtOH (2 mL) was added DIEA(0.2 mL, 1.16 mmol). The resultant mixture was heated at 145° C. for 4.5h in microwave. After TLC and MS showed completion of the reaction, themixture was cooled to room temperature and diluted with EtOAc (20 mL).The organic layer was washed with water (20 mL), brine, dried overanhydrous Na₂SO₄, filtered and evaporated to dryness. The resultingresidue was purified by ISCO (SiO₂: CH₂Cl₂/MeOH 0 to 10% and SiO₂:EthOAc/MeOH 0 to 8%) to give the title compound as off-white solid 1-61(184 mg, 65%), which was recrystallized from Teac/Hexane (157 mg). mp.150° C. (decomposed). ¹H NMR (300 MHz, DMSO-d₆) δ 11.92 (brs, NH), 7.82(brs, NH), 7.74-7.72 (m, 2H), 7.60 (d, J=6.2 Hz, 1H), 7.44 (dd. J=2.2Hz, 6.2 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 5.19 (m, 1H), 3.46 (s, 2H) 3.03(s, 3H), 1.37 (d, J=6.6 Hz, 1H). LCMS: Rt 4.08 min, m/z 370.1 [M+H]⁺.

Example 33(S)-2-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one(I-62)

Step-1: 2-chloro-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one

A mixture of 2-chloro-5-iodopyrimidin-4-amine (256 mg, 1 mmol),3-ethoxy-3-oxopropylzinc bromide 2 (6 mL, 0.5 M in THF, 3 mmol) andPd(PPh₃)₄(116 mg, 0.1 mmol) in anhydrous benzene (5 mL) was refluxedunder N₂ overnight. After removal of solvents under reduced pressure,the residue was purified on ISCO (40 g silica gel column, EtOAc/hexanes0-100%; then 20 g silica gel column, MeOH/dichloromethane 010%) to givethe title compound as an off-white solid (29 mg, 16%).

Step-2:(S)-2-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one(I-62)

A mixture of (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride III-1 (102 mg, 0.39 mmol),2-chloro-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (36 mg, 0.20 mmol)and N,N-diisopropylethylamine (100 μL, 0.59 mmol) in EtOH (1.5 mL) washeated in the microwave at 150° C. for two hours. After removal ofsolvent under reduced pressure, the residue was purified on ISCO (20 gsilica gel column, MeOH/dichloromethane 0-10%) to give the desiredproduct as an off-white solid. It was dissolved in acetonitrile, mixedwith water and lyophilized to afford the title compound I-62 as whitefoam (25 mg, 35%). ¹H NMR (300 MHz, MeOD-d₃) δ ppm: 7.92 (s, 1H), 7.82(s, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.45 (dd, J=8.8, 2.2 Hz, 1H), 7.30 (d,J=8.8 Hz, 1H), 5.24 (m, 1H), 2.75 (m, 2H), 2.56 (m, 2H), 1.50 (d, J=6.9Hz, 3H). LCMS (Method 3): 97% pure @254 nm, Rt 5.30 min, m/z 370, 372[M+H]⁺.

TABLE 4 The compounds listed in Table 1 were prepared using methodssimilar to the one described for the preparation of I-42 to I-62.

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

TABLE 5 LCMS signal and NMR chemical shifts of each compound listed inTable 4. Compounds LCMS^(a) ¹H NMR (300 MHz) δ ppm Chemical Name I-42m/z: 383.16 3-[(1S)-1-({1-acetyl-1H,2H,3H- (M + H)⁺pyrrolo[3,2-c]pyridin-4- Rt (min): 0.88 yl}amino)ethyl]-6-chloro-1,2-dihydroquinolin-2-one I-43 m/z: 419.10 6-chloro-3-[(1S)-1-({1- (M + H)⁺methanesulfonyl-1H,2H,3H- Rt (min): 0.93 pyrrolo[3,2-c]pyridin-4-yl}amino)ethyl]-1,2- dihydroquinolin-2-one I-44 m/z: 399.133-[(1S)-1-({1-acetyl-1H,2H,3H- (M + H)⁺ pyrido[3,4-b][1,4]oxazin-5- Rt(min): 0.89 yl}amino)ethyl]-6-chloro-1,2- dihydroquinolin-2-one I-45m/z: 341.05 6-chloro-3-[(1S)-1-({1H- (M + H)⁺pyrazolo[3,4-d]pyrimidin-6- Rt (min): 0.98 yl}amino)ethyl]-1,2-dihydroquinolin-2-one I-46 m/z: 428.13 ¹H-NMR (300 MHz, CDCl3, 50° C.)6-chloro-3-[(1S)-1-{[1-(2- (M + H)⁺ δ: 10.5 (broad s, 0.8H), 7.90 (s,methylpropyl)-2-oxo-1H,2H,4H- Rt (min): 1H), 7.62 (s, 1H), 7.49 (s, 1H),pyrimido[4,5-d][1,3]oxazin-7- 1.2884 7.40 (d, J = 7.98, 1H), 7.16 (d, J= 8.52, yl]amino}ethyl]-1,2- 1H), 6.00 (d, J = 6.84, 1H), 5.27 (m,dihydroquinolin-2-one 1H), 5.06 (s, 2H), 3.82 (m, 2H), 2.05 (m, 1H),1.61 (d, J = 6.87, 3H) 0.82 (m, 6H) I-47 m/z: 385.98 ¹H-NMR (300 MHz,CDCl3) δ: 6-chloro-3-[(1S)-1-({1-methyl-2- (M + H)⁺ 11.40 (broad s,0.8H), 7.90 (s, 1H), oxo-1H,2H,4H-pyrimido[4,5- Rt (min): 1.07 7.67 (s,1H), 7.50 (broad s, 1H), d][1,3]oxazin-7-yl}amino)ethyl]- 7.40 (dd, J =2.19, 8.79, 1H), 7.27 (m, 1,2-dihydroquinolin-2-one 1H), 6.17 (d, J =8.49, 1H), 5.30 (m, 1H), 5.07 (s, 2H), 3.31 (s, 3H), 1.62 (d, J = 6.87,3H). I-48 m/z: 493.20 ¹H NMR (300 MHz, DMSO-d6): δ6-chloro-3-[(1S)-1-({1-methyl-2- (M + H)⁺ 11.78 (br s, 1H), 8.61 (d, J =4.9 Hz, oxo-1H,2H,4H-pyrimido[4,5- Rt (min): 1.24 1H), 7.98 (br s, 1H),7.91-7.85 (m, d][1,3]oxazin-7-yl}amino)ethyl]-7- 1H), 7.79 (s, 1H),7.75-7.62 (m, (pyridin-2-ylmethoxy)-1,2- 2H), 7.56 (d, J = 7.7 Hz, 1H),dihydroquinolin-2-one 7.39-7.35 (m, 1H), 7.01 (s, 1H), 5.28 (s, 2H),5.16-5.09 (m, 3H), 3.24-3.20 (m, 3H), 1.38 (d, J = 6.9 Hz, 3H). I-49m/z: 372.1 ¹H NMR (300 MHz, DMSO-d6, 6-chloro-3-[(1S)-1-({2-oxo- (M +H)⁺ 80° C.): δ ppm: 11.70 (br s 1H), 1H,2H,4H-pyrimido[4,5- Rt (min):3.78* 10.38 (br s, 1H), 7.98 (s, 1H), d][1,3]oxazin-7-yl}amino)ethyl]-7.78 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H), 1,2-dihydroquinolin-2-one 7.45(dd, J1 = 8.5 Hz, J2 = 2.4 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.15 (brd, 1H), 5.15-5.25 (m, 1H), 5.13 (s, 2H), 1.45 (d, J = 6.6 Hz, 3H). I-50m/z: 416.05 1H NMR (300 MHz, DMSO-d6): δ 6-chloro-7-methoxy-3-[1-({1-(M + H)⁺ ppm 11.81 (s, 1 H), 7.99 (br s, 1 H), methyl-2-oxo-1H,2H,4H- Rt(min): 1.09 7.62-7.80 (m, 3 H), 6.94 (s, 1 H),pyrimido[4,5-d][1,3]oxazin-7- 5.07-5.21 (m, 3 H), 3.87 (s, 3 H),yl}amino)ethyl]-1,2- 3.23 (br s, 3 H), 1.38 (d, J = 7.04 Hz,dihydroquinolin-2-one 3 H). I-51 m/z: 416.126-chloro-7-methoxy-3-[(1S)-1-({1- (M + H)⁺ methyl-2-oxo-1H,2H,4H- Rt(min): 1.16 pyrimido[4,5-d][1,3]oxazin-7- yl}amino)ethyl]-1,2-dihydroquinolin-2-one I-52 m/z: 416.12 6-chloro-7-methoxy-3-[(1R)-1-({1-(M + H)⁺ methyl-2-oxo-1H,2H,4H- Rt (min): 1.16pyrimido[4,5-d][1,3]oxazin-7- yl}amino)ethyl]-1,2- dihydroquinolin-2-oneI-53 m/z: 404.09 ¹H NMR (300 MHz, DMSO-d6): δ6-chloro-7-fluoro-3-[(1R)-1-({1- (M + H)⁺ ppm 7.91-8.02 (m, 2 H), 7.74(br s, methyl-2-oxo-1H,2H,4H- Rt (min): 1.22 2 H), 7.13-7.26 (m, 2 H),pyrimido[4,5-d][1,3]oxazin-7- 5.06-5.21 (m, 3 H), 3.23 (br s, 3 H),yl}amino)ethyl]-1,2- 1.39 (d, J = 6.74 Hz, 3 H). dihydroquinolin-2-oneI-54 m/z: 387.00 ¹H NMR (300 MHz, DMSO-d₆)6-chloro-3-[(1S)-1-({1-methyl-2- (M + H)⁺ δ ppm 12.39 (s, 1 H), 8.46 (s,1 oxo-1H,2H,4H-pyrimido[4,5- Rt (min): 1.88 H), 8.26 (s, 1 H), 7.95 (s,1 H), d][1,3]oxazin-7-yl}amino)ethyl]- 7.73 (s, 1 H), 6.78 (s, 1 H),1,2-dihydro-1,8-naphthyridin-2- 5.03-5.18 (m, 3 H), 3.40 (s, 3 H),), one1.38 (d, J = 7.04 Hz, 3H) I-55 m/z: 414.08 ¹H NMR (300 MHz, CD₃OD): δ6-chloro-3-[(1S)-1-{[3-(2- (M + H)⁺ 7.92 (s, 1H), 7.77 (s, 1H), 7.58 (d,J = 2.2 Hz, methylpropyl)-2-oxo-2H,3H- Rt (min): 1.43 1H), 7.44 (dd, J =8.6 Hz, 2.2 Hz, [1,3]oxazolo[4,5-d]pyrimidin-5- 1H), 7.33 (d, J = 8.8Hz, 1H), yl]amino}ethyl]-1,2- 5.26 (q, J = 6.9 Hz, 1H),dihydroquinolin-2-one 3.59-3.48 (m, 2H), 2.06 (bs, 1H), 1.51 (d, J = 6.9Hz, 3H), 0.79 (bs, 6H). I-56 m/z: 358.04 ¹H NMR (300 MHz, CD₃OD): δ6-chloro-3-[(1S)-1-({2-oxo- (M + H)⁺ 7.81 (s, 1H), 7.66 (s, 1H), 7.31(d, J = 2.2 Hz, 2H,3H-[1,3]oxazolo[4,5- Rt (min): 0.96 1H), 7.45 (dd, J= 8.8 Hz, 2.2 Hz, d]pyrimidin-5-yl}amino)ethyl]-1,2- 1H), 7.30 (d, J =8.8 Hz, 1H), dihydroquinolin-2-one 5.21 (q, J = 6.9 Hz, 1H), 1.52 (d, J= 6.8 Hz, 3H). I-57 m/z: 372.05 ¹H NMR (300 MHz, CDCl3): δ6-chloro-3-[(1S)-1-({3-methyl-2- (M + H)⁺ 10.94 (s, 1H), 7.89 (s, 1H),7.67 (s, 1H), oxo-2H,3H-[1,3]oxazolo[4,5- Rt (min): 7.51 (d, J = 2.2 Hz,1H), 7.50 (dd, J = 8.8 Hz, d]pyrimidin-5-yl}amino)ethyl]-1,2- 1.1649 2.2Hz, 1H), 6.05 (d, J = 8.2 Hz, dihydroquinolin-2-one 1H), 5.28 (m, 1H),3.32 (s, 3H), 1.63 (d, J = 6.9 Hz, 3H) I-58 m/z: 371.08 ¹H NMR (300 MHz,DMSO-d6) δ: 6-chloro-3-[(1S)-1-[(9-methyl-8- (M + H)⁺ 11.93 (s, 1H),10.67 (s, 1H), 7.74 (s, oxo-8,9-dihydro-7H-purin-2- Rt (min): 0.88 1H),7.71 (d, J = 2.5 Hz, 1H), yl)amino]ethyl]-1,2- 7.70 (s, 1H), 7.46 (dd, J= 8.8, 2.5 Hz, dihydroquinolin-2-one 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.18(d, J = 7.7 Hz, 1H), 5.12 (m, 1H), 3.16 (s, 3H), 1.37 (d, J = 6.9 Hz,3H). LCMS (LCMS method 1, APCI): 98% pure @ 254 nm, RT = 3.87 min, m/z =371, 373 [M + H]+. I-59 m/z: 357.04 ¹H NMR (300 MHz, DMSO-d6) δ:6-chloro-3-[(1S)-1-[(8-oxo-8,9- (M + H)⁺ 11.92 (s, 1H), 11.27 (br.s,1H), dihydro-7H-purin-2- Rt (min): 0.79 10.40 (s, 1H), 7.71 (s, 1H),7.70 (d, yl)amino]ethyl]-1,2- J = 2.2 Hz, 1H), 7.67 (s, 1H),dihydroquinolin-2-one 7.46 (dd, J = 8.8, 2.2 Hz, 1H), 7.28 (d, J = 8.8Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.07 (m, 1H), 1.36 (d, J = 6.9 Hz,3H) I-60 m/z: 356.10 ¹H NMR (300 MHz, DMSO-d6) δ6-chloro-3-[(1S)-1-({6-oxo- (M + H)⁺ 12.07 (brs, NH), 11.92 (brs, NH),5H,6H,7H-pyrrolo[2,3- Rt (min): 0.79 7.96 (brs, NH), 7.81 (m, 1H),d]pyrimidin-2-yl}amino)ethyl]-1,2- 7.77 (d, J = 2.2 Hz, 1H), 7.53 (dd, J= 2.2 Hz, dihydroquinolin-2-one 6.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H),5.18 (m, 1H), 3.47 (s, 2H), 1.45 (d, J = 6.6 Hz, 1H) I-61 m/z: 370.04 ¹HNMR (300 MHz, DMSO-d6) δ 6-chloro-3-[(1S)-1-({7-methyl-6- (M + H)⁺ 11.92(brs, NH), 7.82 (brs, NH), oxo-5H,6H,7H-pyrrolo[2,3- Rt (min): 0.97.74-7.72 (m, 2H), 7.60 (d, J = 6.2 Hz,d]pyrimidin-2-yl}amino)ethyl]-1,2- 1H), 7.44 (dd, J = 2.2 Hz, 6.2 Hz,dihydroquinolin-2-one 1H), 7.27 (d, J = 8.8 Hz, 1H), 5.19 (m, 1H), 3.46(s, 2H), 3.03 (s, 3H), 1.37 (d, J = 6.6 Hz, 1H). I-62 m/z: 370.04 ¹H NMR(300 MHz, MeOD-d3) δ: 6-chloro-3-[(1S)-1-({7-oxo- (M + H)⁺ 7.92 (s, 1H),7.82 (s, 1H), 7.61 (d, J = 2.2 Hz, 5H,6H,7H,8H-pyrido[2,3- Rt (min):0.88 1H), 7.45 (dd, J = 8.8, 2.2 Hz, d]pyrimidin-2-yl}amino)ethyl]-1,2-1H), 7.30 (d, J = 8.8 Hz, 1H), dihydroquinolin-2-one 5.24 (m, 1H), 2.75(m, 2H), 2.56 (m, 2H), 1.50 (d, J = 6.9 Hz, 3H) ^(a)LCMS data aredetermined by Method 4.

Example 34 IDH1-R132H and IDH1-R132C Enzymatic Assay

Assays were performed in a 384-well black plate. An aliquot of 250 nL ofcompound was incubated with 10 μL of 30 nM IDH1-R132H or 10 nMIDH1-R132C recombinant protein in assay buffer (50 mM Tris pH=7.5, 150mM NaCl, 5 mM MgCl₂, 0.1% (w/v) Bovine Serum Albumin, and 0.01% TritonX-100) in each well at 25° C. for 15 minutes. After the plate wascentrifuged briefly, an aliquot of 10 μL of 2 mM α-ketoglutarate and 20μM NADPH solution prepared in assay buffer was then added to each welland the reaction was maintained at 25° C. for 45 minutes. An aliquot of10 μL of diaphorase solution (0.15 U/mL diaphorase and 30 μM Resazurinin assay buffer) was added to each well. The plate was maintained at 25°C. for 15 minutes and then read on a plate reader with excitation andemission wavelengths at 535 nm and 590 nm, respectively. The IC₅₀ of agiven compound was calculated by fitting the dose response curve ofinhibition of NADPH consumption at a given concentration with the fourparameter logistic equation.

Example 35 Cellular 2-HG Assay Using HCT116 Mutant IDH1 Cells

HCT116 isogenic IDH1-R132H and IDH1-R132C mutant cells were cultured ingrowth media (McCoy's 5A, 10% fetal bovine serum, 1×antibiotic-antimycotic solution and 0.3 mg/mL G418) in 5% CO₂ in anincubator at 37° C. To prepare the assay, cells were trypsinized andresuspended in assay media (McCoy's 5A with no L-glutamine, 10% fetalbovine serum, 1× antibiotic-antimycotic solution and 0.3 mg/mL G418). Analiquot of 10,000 cells/100 L was transferred to each well of a clear96-well tissue culture plate. The cells were incubated in 5% CO₂ at 37°C. in an incubator overnight to allow for proper cell attachment. Analiquot of 50 μL of compound containing assay media were then added toeach well and the assay plate was kept in 5% CO₂ at 37° C. in anincubator for 24 hours. The media was then removed from each well and150 μL of a methanol/water mixture (80/20 v/v) was added to each well.The plates were kept at −80° C. freezer overnight to allow for completecell lysis. An aliquot of 125 μL of extracted supernatant was analyzedby RapidFire high-throughout-mass spectrometry (Agilent) to determinethe cellular 2-HG level. The IC₅₀ of a given compound was calculated byfitting the dose response curve of cellular 2-HG inhibition at a givenconcentration with the four parameter logistic equation

Table 6 below provides activity of each compound according to the legendthat “++++” indicates an inhibition at a concentration <0.1 μM; “+++”indicates inhibition at a concentration between 0.1 μM and 1 μM of thedisclosed compound; “++” indicates inhibition at a concentration from 1μM to 10 μM of the disclosed compound; and “+” indicates inhibition at aconcentration >10 μM.

TABLE 6 Results of the illustrative compounds of Formula I inIDH1-R132H, IDH1-R132C, IDH1-MS-HTC116-R132H, and IDH1-MS-HTC116-R132Cassays. Enzyme Enzyme HCT116 HCT116 IDH1 IDH1 IDH1 IDH1 R132H R132CR132H R132C IC50 IC50 IC50 IC50 No (uM) (uM) (uM) (uM) I-1 +++ +++ I-2+++ I-3 +++ I-4 +++ + I-5 +++ I-6 ++ I-7 ++ I-8 ++ I-9 ++ I-10 ++ I-11++ I-12 + I-13 + I-14 + I-15 + I-16 + I-17 + I-18 + I-19 + I-20 ++I-21 + I-22 + I-23 + I-24 + I-25 + I-26 + I-27 + I-28 + I-29 + I-30 +I-31 + I-32 + I-33 + I-34 + I-35 + I-36 + I-37 + I-38 + I-39 + I-40 +I-41 ++ I-42 +++ ++ I-43 ++ I-44 ++ + I-45 +++ ++ +++ +++ I-46 ++++ ++++I-47 ++++ ++++ ++++ ++++ I-48 ++++ ++++ ++++ ++++ I-49 ++++ +++ ++++ +++I-50 ++++ ++++ ++++ ++++ I-51 ++++ ++++ ++++ ++++ I-52 +++ ++ I-53 ++ +I-54 I-55 ++++ ++++ +++ ++ I-56 ++++ +++ ++ + I-57 ++++ +++ +++ +++ I-58+++ ++ +++ ++ I-59 ++ ++ I-60 +++ ++ +++ ++ I-61 +++ +++ +++ +++ I-62 ++++

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1. A compound of formula I:

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate,prodrug, isomer, or tautomer thereof, wherein: each W₁ and W₂ isindependently CH, CF, or N; W₃ is CF, CR₂, or N; U is N or CR₆; V is Nor CR₉; Z is N or C;

indicates a single or double bond but never two double bonds adjacent toone another in the ring in which the

occurs; A and B, A and R6, or B and R₉ are taken together with the atomsto which they are attached and form an aryl or a 5 to 7-memberedheterocyclyl or heteroaryl ring system which can be further substitutedwith one or more R₁₀ substituents; A and B, when not part of the fusedaryl, heteroaryl, or 5 to 7-membered heterocyclyl, are eachindependently H, R6, CN, C₁-C₆ alkyl, or C₁-C₆ alkoxy; R₁ isindependently H, OH, CN, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, 3 to 8-membered heterocyclyl,aryl, or heteroaryl, wherein each C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocyclyl, aryl, or heteroaryl isoptionally substituted one or more times with substituents selected fromthe group consisting of halogen, OH, NH₂, CN, C₁-C₆ alkyl, and C₁-C₆alkoxy; R₂ is independently H, OH, CN, halogen, CF₃, CHF₂, C₁-C₆ alkyl,C₁-C₆ alkoxy, NH₂, —O(CH₂)_(n)R₇, —O(CH₂)_(n)C(O)NHR₇,—O(CH₂)_(n)C(O)R₇, NHR₇, —N(R₇)(R₈), NHC(O)R₇, NHS(O)R₇, NHS(O)₂R7,NHC(O)OR₇, NHC(O)NHR₇, —S(O)₂NHR₇, NHC(O)N(R₈)R₇, OCH(R₇)(R₈), or—CH(R₇)(R₈), wherein C₁-C₆ alkyl, C₁-C₆ alkoxy is optionally substitutedwith one or more substituents selected from the group consisting ofC₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, or 3 to 8-membered heterocyclyl substituted with one or morehalogen, 3 to 8-membered heterocyclyl, aryl, -heteroaryl-C(O)NH₂, andheteroaryl; R₃ is H or C₁-C₆ alkyl; R₄ and R₅ are independently H,halogen, CH₂OH, C₁-C₃ alkyl, or C₁-C₃ haloalkyl, or R₄ and R₅ whencombined can form a C₃-C₆ cycloalkyl or 3 to 8-membered heterocyclyl; R₆is H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, 3 to8-membered heterocyclyl, aryl, or heteroaryl; R₇ and R₈ areindependently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, 3 to 8-membered heterocyclyl, aryl, andheteroaryl; or when combined R₇ and R₈ can form a 3 to 8-memberedheterocyclyl or heteroaryl ring; and R₉ is independently selected fromthe group consisting of H, ═O, halogen, OH, CN, —CH₂CN, C₁-C₆ alkyl,R₇S(O)₂—, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl,C₃-C₈ cycloalkylalkyl, 3 to 8-membered heterocyclyl, aryl, andheteroaryl, wherein alkyl, alkoxy, alkenyl, cycloalkyl, cycloalkylalkyl,3 to 8-membered heterocyclyl, aryl, and heteroaryl are optionallyfurther substituted with one or more substituents selected from thegroup consisting of OH, halogen, C₁-C₆ alkoxy, NH₂, R₇S(O)₂—, CN, C₃-C₈cycloalkyl, 3 to 8-membered heterocyclyl, aryl, heteroaryl, and R₇S(O)—;each R₁₀ is independently H, OH, CN, ═O, —COOR₁₁, —C(O)R₁₁, —CH₂CN,C₁-C₆ alkyl, C₁-C₆ haloalkyl R₁₁S(O)₂—, C₁-C₆ alkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, C₃-C₈heterocyclyl, aryl, or heteroaryl; and each R₁₁ is independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, 3 to 8-memberedheterocyclyl, aryl, or heteroaryl; provided that: (1) when A and B or Aand R₆ form a 1,4-dioxane ring, R₁ and R₂ are not both methyl; (2) whenA and B or A and R₆ form a 1,3-dioxolane ring, R₁ is not H or methyl;(3) when A and B or A and R₆ form a pyridine ring, R₁ is not H or R₂ isnot methyl; (4) when A and B or A and R₆ form a pyrazole ring, R₁ is notH, ethyl, or ethoxy; (5) when A and B or A and R₆ form a pyrazole ringand R₁ is methyl, R₂ is not H; or (6) when A and B or A and R₆ form aphenyl ring, R₁ is not H.
 2. The compound of claim 1 having a FormulaIa:

wherein: the C ring is pyrrolidinyl, piperidinyl, phenyl, thienyl,oxazolyl, dioxanyl, dioxolanyl, thiazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl,pyridyl, pyrimidinyl, pyrrolyl, furyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl,pyrimidinyl, morpholinyl, thiomorpholinyl, oxazolonyl, oxazinonyl,dihydrooxazinonyl, imidazolonyl, pyrrolonyl, thiazolonyl,dihydropyridinonyl, dihydrothiazinedioxide, dihydrodioxinyl,dihydropyranonyl, dihydrothiophenedioxide, piperidinonyl, ordihydrooxazinony; and R₁₀ is independently H, OH, CN, ═O, —COOR₁₁,—C(O)R₁₁, —CH₂CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl R₁₁S(O)₂—, C₁-C₆ alkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl,C₃-C₈ heterocyclyl, aryl, or heteroaryl; and each R₁₁ is independentlyH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, C₃-C₈ heterocyclyl,aryl, or heteroaryl.
 3. The compound of claim 2, wherein R₁₀ is methyl,ethyl, isopropyl, or isobutyl.
 4. The compound of claim 1 having aFormula Ib:

wherein: the C ring is pyrrolidinyl, piperidinyl, phenyl, thienyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl,oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl,pyrrolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, dazolyl,pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, pyrimidinyl, morpholinyl,thiomorpholinyl, oxazolonyl, oxazinonyl, dihydrooxazinonyl,imidazolonyl, pyrrolonyl, thiazolonyl, dihydropyridinonyl,dihydrothiazinedioxide, dihydrodioxinyl, dihydropyranonyl,dihydrothiophenedioxide, piperidinonyl, or dihydrooxazinonyl; R₁₀ isindependently H, OH, CN, ═O, —COOR₁₁, —C(O)R₁₁, —CH₂CN, C₁-C₆ alkyl,C₁-C₆ haloalkyl R₁₁S(O)₂—, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, C₃-C₈ heterocyclyl, aryl, orheteroaryl; and each R₁₁ is independently H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,C₃-C₈ cycloalkylalkyl, C₃-C₈ heterocyclyl, aryl, or heteroary.
 5. Thecompound of claim 4, wherein R₁₀ is methyl, ethyl, isopropyl, orisobutyl.
 6. The compound of claim 1, wherein R₄ and R₅ are H.
 7. Thecompound of claim 1, wherein R₄ is H and R₅ is methyl.
 8. The compoundof claim 1, wherein R₄ is H and R₅ is (S)-methyl.
 9. The compound ofclaim 1, wherein R₄ and R₅ are halogen.
 10. The compound of claim 1,wherein R₄ is F and R₅ is methyl.
 11. The compound of claim 1, whereinR₄ and R₅ can combine to form a C₃-C₅ cycloalkyl.
 12. The compound ofany of the foregoing claims, wherein W₁, W₂ and W₃ are CH or CF.
 13. Thecompound of any of the foregoing claims, wherein W₁, W₂, or W₃ is N. 14.The compound of any of the foregoing claims, wherein R₁ is halogen. 15.The compound of claim 14, wherein R₁ is chloro.
 16. The compound of anyof the foregoing claims, wherein R₂ is H or C₁-C₆ alkoxy.
 17. Thecompound of any of the foregoing claims, wherein R₂ is C₁-C₆ alkoxysubstituted with heteroaryl or C₃-C₈ heterocyclyl.
 18. The compound ofclaim 1 selected from the group consisting of:3-{[(1,3-benzoxazol-4-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(isoquinolin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}naphthalene-1-carbonitrile;6-chloro-3-{[(quinolin-8-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2,3-dihydro-1-benzofuran-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-one;7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3,4-dihydro-2H-1,4-benzoxazin-3-one;3-({[2-(1H-1,3-benzodiazol-5-yl)-1H-1,3-benzodiazol-5-yl]amino}methyl)-6,7-dimethoxy-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(isoquinolin-8-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3,4-dihydro-2H-1-benzopyran-8-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-1H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-methoxy-3-{[(2-methyl-1,3-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({[1,2,4]triazolo[4,3-b]pyridazin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;3-{[(1H-1,3-benzodiazol-5-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-{[(1,3-benzothiazol-6-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-{[(quinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-({[2-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;3-{[(1,3-benzothiazol-5-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;3-{[(2,3-dihydro-1,4-benzodioxin-6-yl)amino]methyl}-6-methoxy-1,2-dihydroquinolin-2-one;3-{[(1H-indazol-6-yl)amino]methyl}-6,7-dimethyl-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-methylquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2,3-dihydro-1,4-benzodioxin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-{[(1H-indazol-6-yl)amino]methyl}-6-methoxy-1,2-dihydroquinolin-2-one;6-methoxy-3-{[(2-methylquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-{[(1,3-benzothiazol-6-yl)amino]methyl}-6-methoxy-1,2-dihydroquinolin-2-one;6,7-dimethyl-3-{[(2-methylquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-methoxy-3-{[(quinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-{[(1,3-benzothiazol-6-yl)amino]methyl}-6,7-dimethyl-1,2-dihydroquinolin-2-one;6-tert-butyl-3-{[(1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-[(1S)-1-({1-acetyl-1H,2H,3H-pyrrolo[3,2-c]pyridin-4-yl}amino)ethyl]-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-methanesulfonyl-1H,2H,3H-pyrrolo[3,2-c]pyridin-4-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;3-[(1S)-1-({1-acetyl-1H,2H,3H-pyrido[3,4-b][1,4]oxazin-5-yl}amino)ethyl]-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[1-(2-methylpropyl)-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-7-methoxy-3-[1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-7-methoxy-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-7-methoxy-3-[(1R)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-7-fluoro-3-[(1R)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydro-1,8-naphthyridin-2-one;6-chloro-3-[(1S)-1-{[3-(2-methylpropyl)-2-oxo-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({3-methyl-2-oxo-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-[(9-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-[(8-oxo-8,9-dihydro-7H-purin-2-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({6-oxo-5H,6H,7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({7-methyl-6-oxo-5H,6H,7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;and6-chloro-3-[(1S)-1-({7-oxo-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one.19. The compound of claim 1 selected from the group consisting of:6-chloro-3-[(1S)-1-({1-cyclopropyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[2-oxo-1-(propan-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-1H,3H-2λ⁶,1,5,7-[1λ⁶,2]thiazolo[3,4-d]pyrimidine-2,2-dione;6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-1H,3H-2λ⁶,1,5-[1λ⁶,2]thiazolo[4,3-c]pyridine-2,2-dione;6-chloro-3-[(1S)-1-({3-methyl-2-oxo-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H-[1,3]thiazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-oxo-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2H,3H-1λ⁶,2,5-[1λ⁶,2]thiazolo[4,5-c]pyridine-1,1-dione;5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-1-one;6-chloro-3-[(1S)-1-({3-oxo-1H,2H,3H,4H-pyrimido[4,5-c]pyridazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({6-oxo-6H-pyrano[3,2-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H-pyrido[3,4-b]pyrazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({3-oxo-1H,2H,3H,4H-pyrido[4,3-c]pyridazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-8-methyl-7,8-dihydropteridin-7-one;6-chloro-3-[(1S)-1-({2-methyl-1-oxo-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[6-(2-oxo-1,3-oxazolidin-3-yl)-[1,3]oxazolo[4,5-c]pyridin-4-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-[1,3]oxazolo[4,5-c]pyridine-7-carbonitrile;N-(4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-[1,3]oxazolo[4,5-c]pyridin-6-yl)acetamide;3-[(1S)-1-[(1H-1,3-benzodiazol-4-yl)amino]ethyl]-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1H-imidazo[4,5-c]pyridin-4-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1H-imidazo[4,5-c]pyridine-7-carbonitrile;6-chloro-3-[(1S)-1-({1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({[1,2,4]triazolo[4,3-b]pyridazin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-1H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3,4-dihydro-2H-1,4-benzoxazin-3-one;7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-one;6-chloro-3-[(1S)-1-{[1-(2-methylpropyl)-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({3-methyl-2-oxo-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[7-oxo-8-(propan-2-yl)-5H,6H,7H,8H-[1,3]diazino[4,5-d]pyrimidin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({8-ethyl-7-oxo-5H,6H,7H,8H-[1,3]diazino[4,5-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[2-oxo-1-(propan-2-yl)-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;7-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-2,4-dihydro-1H-3,1-benzoxazin-2-one;6-chloro-3-[(1S)-1-({1-ethyl-2-oxo-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;7-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2,4-dihydro-1H-3,1-benzoxazin-2-one;3-[(1S)-1-({1-acetyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-5-yl}amino)ethyl]-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[1-(2-methylpropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[8-(2-methylpropyl)-7-oxo-5H,6H,7H,8H-[1,3]diazino[4,5-d]pyrimidin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;7-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-(2-methylpropyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one;6-chloro-3-[(1S)-1-{[1-(2-methylpropyl)-2-oxo-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-4-(2-methylpropyl)-1,2,3,4-tetrahydroquinoxalin-2-one;6-chloro-3-[(1S)-1-{[4-methyl-1-(2-methylpropyl)-3-oxo-1H,2H,3H,4H-pyrido[3,4-b]pyrazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[(4R)-1-methyl-4-(2-methylpropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[9-(2-methylpropyl)-9H-purin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[3-(2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[3-(2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[1-(2-methylpropyl)-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[2-oxo-3-(propan-2-yl)-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[9-(propan-2-yl)-9H-purin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[2-oxo-1-(propan-2-yl)-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-{[6-methyl-7-oxo-8-(propan-2-yl)-5H,6H,7H,8H-[1,3]diazino[4,5-d]pyrimidin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methyl-1-(2-methylpropyl)-1,2,3,4-tetrahydroquinoxalin-2-one;6-chloro-3-[(1S)-1-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-2H,3H-[1,3]oxazolo[4,5-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-1H,2H-[1,3]oxazolo[5,4-d]pyrimidin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1,4-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1,2,3,4-tetrahydroquinoxalin-2-one;6-chloro-3-[(1S)-1-[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]ethyl]-1,2-dihydroquinolin-2-one;6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-2-one;6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-cyclopropyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-cyclobutyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-ethyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-cyclobutyl-2-oxo-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-cyclopropyl-2-oxo-1H,2H,4H-pyrido[4,3-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({5-methyl-6-oxo-5H,6H,7H,8H-pyrido[3,2-d]pyrimidin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-(prop-2-yn-1-yl)-1H-1,3-benzodiazol-3-ium;6-chloro-3-{[(2-ethynyl-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-ethynyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({1-methyl-2-oxo-1H,2H,3H-pyrrolo[3,2-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({2-oxo-1H,2H,3H-pyrrolo[3,2-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-({[(1R)-1-oxo-2,3-dihydro-1λ⁴-benzothiophen-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-[({5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-1,3-dihydro-2,1-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-[({3-tert-butyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-[(1R)-1-{[1-(2-methylpropyl)-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;(4R)-6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-4-(2-methylpropyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-2-one6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-(propan-2-yl)imidazo[1,2-a]pyridin-1-ium;6-chloro-3-({[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-({[3-(propan-2-yl)-2H-indazol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-({[3-(propan-2-yl)-1,2-benzoxazol-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one6-chloro-3-[({3-propyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-ethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-({[(3S)-3-ethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-({[(3S)-3-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-[({3-ethyl-7-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({3-ethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-ethyl-6-methyl-2H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-ethyl-7-methyl-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-methyl-2,3-dihydro-1,2-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-8-carboxamide;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-4-fluoro-2-methyl-1H-1,3-benzodiazol-3-ium;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2,3-dimethylimidazo[1,2-a]pyridin-1-ium;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2,5-dimethylimidazo[1,2-a]pyridin-1-ium;6-chloro-3-({[6-(dimethylamino)-8,9-dimethyl-9H-purin-2-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-{[(5-fluoro-2-methyl-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2,7-dimethyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-fluoro-2-methyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3-methyl-1-benzofuran-5-carbonitrile;6-chloro-3-({[2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl]amino}methyl)-1,2-dihydroquinolin-2-one;5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-cyano-1H-1,3-benzodiazol-1-ide;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1H-indole-2-carbonitrile;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}imidazo[1,2-a]pyridine-2-carbonitrile;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1,3-benzothiazole-2-carbonitrile;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2H-indazole-3-carbonitrile;5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2H-indazole-3-carbonitrile;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methyl-1H-indole-3-carbonitrile;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-7-methyl-1H-indole-3-carbonitrile;5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-7-methyl-1H-indole-3-carbonitrile;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-5-methyl-1H-indole-3-carbonitrile;3-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}isoquinoline-8-carbonitrile;6-chloro-3-{[(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-oxo-2,3-dihydro-1,3-benzoxazole-7-carboxamide;6-chloro-3-{[(7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methoxy-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({4-methyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({2-oxo-2H,3H-[1,3]oxazolo[4,5-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-oxo-2H-chromene-8-carboxamide;6-chloro-3-{[(8-methyl-2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(8-methoxy-2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one6-chloro-3-[({8-methyl-2-oxo-2H-pyrano[2,3-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-7-carboxamide;6-chloro-3-{[(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({1,4-dimethyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({3-methyl-2-oxo-2H,3H-[1,3]oxazolo[4,5-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-({[2-(hydroxymethyl)-1,3-benzoxazol-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-({[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-({[3-(hydroxymethyl)-1,2-benzoxazol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-hydroxy-1-benzothiophen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}isoquinoline-5-carboxylate;4-chloro-5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1H-1,3-benzodiazol-3-ium;3-chloro-6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}imidazo[1,2-a]pyridin-1-ium;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-7-formylimidazo[1,2-a]pyridin-1-ium;6-chloro-3-[({2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(5-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(5-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-6-cyano-1H-1,3-benzodiazol-3-ium;6-chloro-5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1H-1,3-benzodiazol-3-ium;7-chloro-5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1H-1,3-benzodiazol-3-ium;6-chloro-3-{[(7-methyl-1H-1,2,3-benzotriazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methoxy-1H-1,2,3-benzotriazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-ethyl-2H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-ethyl-2H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-methyl-1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-methyl-1-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-fluoro-2-methyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-({[6-(dimethylamino)-1H-indol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-hydroxy-3-methyl-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methyl-1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methyl-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3,7-dimethyl-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-cyclopropyl-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methoxy-3-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methoxy-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-oxo-1,3-dihydro-2-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-({[(3R)-3-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3,4-dihydro-2H-1,4-benzoxazin-3-one;6-chloro-3-({[(1R)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-({[(1R)-1-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-({[(1S)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({2,4,5,7-tetraazatricyclo[6.4.0.0^(2,) ⁶]dodeca-1(12),3,5,8,10-pentaen-11-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-cyclopropyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-cyclopropyl-1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-1H-1,2,3-benzotriazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-hydroxy-1H-1,2,3-benzotriazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-oxo-2,3-dihydro-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-1-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-{[(1,2-benzoxazol-5-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methoxy-1,2-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-hydroxy-1-benzothiophen-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-1,2-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-7-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1H,2H,3H,4H-pyrido[2,3-d]pyrimidine-2,4-dione;6-chloro-3-[({1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-({[5-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-[({1-methyl-2-oxo-1H,2H,3H-pyrrolo[2,3-c]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({2-oxo-1H,2H,3H-pyrrolo[2,3-c]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({2-oxo-2H-pyrano[2,3-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({1-methyl-2-oxo-1H,2H-[1,3]oxazolo[5,4-c]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1,5-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methyl-1H-indazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(5-methyl-2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methyl-1-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-fluoro-3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methoxy-7-methyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methoxy-1-benzofuran-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-({[(3R)-3-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-cyclopropyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methoxy-1H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-2H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({3-cyclobutyl-[,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-4-methyl-1,2-dihydro-1,8-naphthyridin-2-one;6-chloro-3-{[(1,8-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3,4-dimethyl-1,2-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(8-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1,5-naphthyridin-2-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(quinoxalin-2-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-({[6-(thiophen-2-yl)-9H-purin-2-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-({[6-(furan-3-yl)-9H-purin-2-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-({[6-(morpholin-4-yl)-9H-purin-2-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-[({4,7-dimethyl-5-oxo-5H,6H-pyrimido[4,5-d][1,3]diazin-2-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-hydroxy-1,2,4-benzotriazin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(5-methyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(5-ethyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methyl-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-ethyl-1H-indol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({5-fluoro-1H-pyrrolo[2,3-b]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;3-[({4-bromo-1H-pyrrolo[2,3-b]pyridin-6-yl}amino)methyl]-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-[({4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)methyl]-1,2-dihydroquinolin-2-one;3-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}quinoxaline-2-carbonitrile;6-chloro-3-{[(5-methyl-1-benzofuran-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methoxy-1-benzofuran-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1,6-naphthyridin-2-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-1H-indazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1,2-benzoxazole-7-carbonitrile;6-chloro-3-{[(7-methyl-1,2-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-{[(1,2-benzoxazol-6-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methyl-1,2-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[({3H-imidazo[4,5-b]pyridin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-chloro-9H-purin-2-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-({[6-(dimethylamino)-9H-purin-2-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-[({imidazo[1,2-a]pyrazin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({imidazo[1,2-b]pyridazin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({3-methyl-3H-imidazo[4,5-b]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-({[5-(methylsulfanyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]amino}methyl)-1,2-dihydroquinolin-2-one;3-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-[1,2,4]triazolo[3,2-c][1,2,4]triazin-4-olate;6-chloro-3-[({[1,2,4]triazolo[1,5-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4,7-dimethyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(5-hydroxy-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-{[(1,3-benzoxazol-6-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;3-{[(1,3-benzoxazol-5-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methyl-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-methyl-1,3-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-hydroxy-1,3-benzothiazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methyl-1,3-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-({[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-[({3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;3-[({8-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-[({3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-({[3-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-[({5-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({7-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({7-methyl-[1,2,3,4]tetrazolo[1,5-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({[1,2,3,4]tetrazolo[1,5-a]pyridin-6-yl}amino)methyl]-1,2-dihydroquinolin-2-one;3-{[(1,2,3-benzoxadiazol-6-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-{[(5-fluoro-1,2,3-benzothiadiazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-{[(2,1,3-benzoxadiazol-5-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-methyl-2,1,3-benzothiadiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methyl-2,1,3-benzothiadiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-methyl-2,1,3-benzothiadiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(4-hydroxy-2,1,3-benzothiadiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-({[7-(propan-2-yl)-1,3-benzoxazol-5-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methyl-1,3-benzothiazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(7-methyl-1,3-benzothiazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-1H,2H,3H-pyrrolo[3,2-c]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-1H,2H,3H-pyrrolo[2,3-c]pyridin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-1H,2H,3H-pyrrolo[2,3-b]pyridin-6-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-1H,2H,3H-pyrrolo[3,2-b]pyridin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-2H,3H-[1,3]oxazolo[4,5-b]pyridin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-1H,2H-[1,3]oxazolo[5,4-b]pyridin-5-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-5H,7H-6λ⁶,1,3-[1λ⁶]thieno[3,4-d]pyrimidine-6,6-dione;6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1H,3H-2λ⁶,1,5,7-[1λ⁶,2]thiazolo[3,4-d]pyrimidine-2,2-dione;2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-5H,6H,8H-7λ⁶,1,3-[1λ⁶]thiopyrano[3,4-d]pyrimidine-7,7-dione;2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-5H,7H,8H-6λ⁶,1,3-[1λ⁶]thiopyrano[4,3-d]pyrimidine-6,6-dione;6-chloro-3-[(1S)-1-({6-methyl-7-oxo-5H,6H,7H,8H,9H-pyrimido[4,5-e][1,4]diazepin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({5H,6H,7H,8H,9H-pyrimido[4,5-b]azepin-2-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({3-methyl-2-oxo-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-5-yl}amino)methyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)methyl]-1,2-dihydroquinolin-2-one;(S)-7-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-6H-pyrido[1,2-a]pyrazin-6-one;(S)-6-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-5H-[1,2,4]oxadiazolo[4,5-a]pyridin-5-one;(S)-6-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-5-one;(S)-6-chloro-3-(1-((5-oxo-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)amino)ethyl)quinolin-2(1H)-one;and(S)-6-chloro-3-(1-((5-oxo-1,5-dihydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)ethyl)quinolin-2(1H)-one.20. A pharmaceutical composition comprising the compound according toclaim 1 and pharmaceutically acceptable carrier.
 21. A method oftreating a disease or disorder associated with mutant isocitratedehydrogenase comprising administering to a patient in need thereof acompound of claim
 1. 22. The method of claim 21, wherein the disease isglioma, glioblastoma multiforme (GBM), acute myeloid leukemia (AML),chondrosarcoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplasticsyndrome (MDS), myeloproliferative disease (MPD) or a solid tumor. 23.The method of claim 21, wherein administering is performed orally,parentally, subcutaneously, by injection, or by infusion.
 24. A methodof inhibiting mutant isocitrate dehydrogenase comprising administeringto a patient in need thereof a compound of claim
 1. 25. A method ofreducing 2-hydroxyglutarate comprising administering to a patient inneed thereof a compound of claim
 1. 26. A compound of any one of claims1-19 for use in the manufacture of a medicament for treating a diseasemediated by mutant isocitrate dehydrogenase.
 27. Use of a compound ofany one of claims 1-19 for treating a disease mediated by mutantisocitrate dehydrogenase.